Slippery, tenaciously adhering hydrophilic polyurethane hydrogel coatings, coated metal substrate materials, and coated medical devices

ABSTRACT

A process for the preparation of slippery, hydrophilic polyurethane hydrogel coating compositions, and materials composed of a polymeric plastic or rubber substrate or a metal substrate with a coating of a slippery, hydrophilic polyurethane hydrogel thereon, such that the coating composition tenaciously adheres to the substrate, are disclosed. The coating compositions and coated materials are non-toxic and biocompatible, and are ideally suited for use on medical devices, particularly, catheters, catheter balloons and stents. The coating compositions, coated materials and coated devices demonstrate low coefficients of friction in contact with body fluids, especially blood, as well as a high degree of wear permanence over prolonged use of the device. The hydrogel coating compositions are capable of being dried to facilitate storage of the devices to which they have been applied, and can be instantly reactivated for later use by exposure to water.

This is a division of application Ser. No. 08/382,478 filed Feb. 1,1995.

BACKGROUND OF THE INVENTION

This invention relates generally to the field of synthetic polymericcoating compositions for polymeric and metal substrates; and, moreparticularly, to hydrophilic hydrogel coating compositions which areslippery and which exhibit tenacious adherence to the substrate to whichthey are applied, and to medical devices bearing such hydrogel coatingsthereon. Still more particularly, this invention relates to hydrophilicpolyurethane hydrogel compositions. The hydrogel coating compositionsand coated substrate materials are biocompatible and suitable for use onmedical devices which come in contact with various body fluids.

In catheters and many other kinds of medical devices, it is oftendesirable to coat various plastic, rubber or metal parts thereof withproducts made from hydrophilic or certain other polymers that areslippery and which produce low coefficients of friction during use.However, one of the problems associated with the utility of suchcoatings is their inability to remain intact and abrasion-resistantduring clinical use in body fluids such as blood. Catheters used inangioplasty, gastroenterology and other medical specialties, arecommonly made of polymeric materials which most often are relativelyhydrophobic and not inherently slippery or biocompatible. A surfacemodification is required in order to reduce the friction between thecatheter and other devices with which they work, such as vascularsheaths, and also to reduce the friction between the vasculature orother anatomical passageways and the catheter itself. Almost allcurrently used catheters have some form of surface modification orcoating applied to them. The ability of the coating to reduce frictionalresistance, its durability, as well as its biocompatibility are the mostimportant functional aspects of an effective surface.

Heretofore, catheters and other medical devices containing synthetic ornatural polymers have often been coated with non-permanent compositionssuch as silicones and other slip agents, fluorocarbons, or hydrogelswhich, however, were usually not cohesively attached to the substratesurfaces. While such coatings can impart a low coefficient of frictionto the surface of a medical device, they typically lack permanence withrespect to frictional wear. Fluorocarbons, moreover, may peel or flakefrom the substrate, or when applied to a soft polymeric substratematerial, may cause an increase in the stiffness of the material. In thecase of marginally polar substrates used for the fabrication ofcatheters and other medical devices such as contact lenses, condoms,gastroenteric feed tubes, endotracheal tubes, and the like, a variety ofpolyurethane based compositions have been suggested as adhesive tiecoats. For such uses the coating must exhibit wear permanence, lowcoefficient of friction in contact with body fluids, as well extremelylow toxicity and good biocompatibility. Whereas a number of polyurethane"tie coats" can improve adhesion to plastics and rubbers, they areoftentimes not compatible enough with respect to the polymer surface ofthe substrates to assure permanence of bonding for the intended medicalapplication. In medical devices this can be a critical requirement formany clinical situations. Particular fields of medical specialties wheresuch factors are important are enumerated below.

In Percutaneous Transluminal Coronary Angioplasty (PTCA) andPercutaneous Transluminal Angioplasty (PTA), the functionalcharacteristics of balloon catheters include trackability throughvasculature, crossability and recrossability of stenotic lesions, andretractability through the guiding catheter and the vascular sheath.These are dynamic functions that are fundamental to a successful andefficient interventional angioplasty procedure. They contribute toreduced trauma to the vasculature. In particular, recrossing of stenoticlesions is crucial to a successful outcome. High pressure angioplastyballoons, typically those made of polyethylene terephthalate (PET), canhave problems with recrossability. This is because the relatively stiffPET material forms "wings" upon deflation after the first dilation. Thewinged profile of the deflated balloon can prevent recrossing of thestenotic lesion for a second dilatation. A durable slippery coating canaid in achieving recrossing of the lesion. Guiding catheters are betterable to traverse tortuosity in the femoral artery and descending aortawith the help of a good slippery coating.

Stent catheters for use in vascular disease benefit from thecharacteristics imparted by a good slippery coating. Stent catheterdelivery systems used in gastroenterology for opening of biliarypassageways also benefit from a slippery coating with regard totraversing passageways leading to the site.

In coronary radiography, diagnostic catheters are used to deliverradiopaque fluid to the coronary arteries for visualization by x-rayfluoroscopy. These catheters benefit in the same way that guidecatheters do from a good slippery coating, by aiding in traversingtortuosity in the femoral artery and the descending aorta.

U.S. Pat. No. 4,118,354 discloses the formation of polyurethanehydrogels which are reaction products of a polyisocyanate, having atleast two isocyanate groups, and a polyether, produced from a pluralityof alkylene oxides, 50 to 90% of which is ethylene oxide, added atrandom to a polyalcohol having at least two terminal hydroxyl groups, bythe dispersal of the prepolymer reaction product into an aqueous liquidphase. Neither the formation of slippery hydrogel barrier coats uponplastic or metal substrates nor the affixation thereof to suchsubstrates by means of covalent chemical bonds to assure durability ofsaid coating upon exertion of dynamic forces thereon are described.

U.S. Pat. No. 4,373,009 describes a method for coating various polymericsubstrates with polyurethane prepolymers containing free isocyanategroups and subjecting the thus coated substrates with a second coatingof water-soluble copolymers of unsaturated monomers containing at leastsome isocyanate-reactive monomers as part of their backbone. It ispostulated that the isocyanate treatment of the substrate results infirmly anchored tie coats even for polymers containing noisocyanate-reactive groups. No convincing evidence of covalent bondingof the urethane tie coat to the substrate is presented, nor is there anyindication that the procedure is suitable for the use in criticalmedical devices where biocompatibility is a significant issue.

U.S. Pat. Nos. 4,459,317 and 4,487,808 discloses a process for treatinga polymer substrate with a first coating of an isocyanate solutioncontaining at least two unreacted isocyanate groups per molecule, and,optionally, a polymer; followed by a second coating of a high molecularweight polyethylene oxide, such that after curing of the isocyanate, thetwo coatings form a hydrophilic polyethylene oxide-polyurea interpolymerhaving a low coefficient of friction. Methods for applying a base coatof low molecular weight aromatic or aliphatic polyisocyanates dissolvedin suitable organic solvents, followed by evaporating the solvent andthen applying a second coat of a high molecular weight polyethyleneoxidepolymer dissolved in an organic solvent are also disclosed. The secondsolution, which may also contain amine catalysts, is then evaporated andthe two coatings are heated at elevated temperature in the presence ofair which must contain enough moisture to react with the isocyanate ofthe first coating. The described processes are relativelytime-consuming. The isocyanate coating is applied by spraying or dippingthe substrate, and no evidence is presented that the isocyanate coatingundergoes any reaction with the substrate surface to make it betteradhering to the substrate surface. Medical devices made from a polymersubstrate to which the coating has been applied, for use in bodycavities, including especially the urethra, are also disclosed. Use ofthe coatings and coated medical devices in a blood medium, however, isnot specifically disclosed, and it is believed that In the absence ofbonding of the isocyanate coating to the substrate itself, the coatingsand coated medical devices ultimately do not demonstrate the desireddegree of permanence, especially in a blood environment.

U.S. Pat. No. 4,642,267 discloses a hydrophilic polymer blend whichcontains a thermoplastic polyurethane having no reactive isocyanategroups and a hydrophilic poly (N-vinyl lactam). The blend is said to beslippery in aqueous environments and is used as a low-friction coatingfor various substrates. Its use and performance in blood is notdisclosed.

Published PCT Patent Application WO 89/09246 describes the use of shapedstructures having polymer or metal substrate surfaces coated withcrosslinked hydrophilic polymers, such as polyvinylpyrrolidone. Thecoated structures are said to be durable and exhibit a low coefficientof friction when wet. The use of polyethylene terephthalate (PET)substrates, which are often used in balloons for angioplasty catheters,is described. Crosslinking between the substrate and the coating isachieved by subjecting a hydrophilic polymer deposited on the substrateto thermally activated free radical initiators, UV light activated freeradical initiation, or E-beam radiation. The adherence of thecrosslinked hydrophilic polymer to the substrate surface is beleived tobe due to physical forces rather than to chemical bonding. Adisadvantage of the process is that neither the thermally activated freeradical initiators nor the UV initiators are biocompatible or suitablefor medical uses. Furthermore, E-beam radiation applied to certainmaterials such as fluorocarbon polymers, which are often employed inmedical devices, can be detrimental to these materials.

U.S. Pat. No. 4,990,357 describes coating compositions containingcombinations of chain-extended hydrophilic thermoplasticpolyetherurethane polymers with a variety of hydrophilic high molecularweight non-urethane polymers, such as polyvinylpyrrolidone. The coatingsare made lubricious by contact with an aqueous liquid. The coatingsadhere to a variety of polymeric substrates, including polyvinylchloride(PVC) and polyurethane (PU). A disadvantage of the coating compositionsis that neither the thermoplastic polyurethane polymer, nor thehydrophilic non-urethane polymer can react with one another. Hence, itis not expected that these coatings give acceptable adhesion to most ofthe plastic substrates used in angioplasty devices.

U.S. Pat. No. 4,906,237 discloses the use of an osmolality-increasingcompound such as glucose, sorbitol, sodium chloride, sodium citrate andsodium benzoate to improve the slipperiness and wetability of a surfacecoating for a polymeric substrate material which has first been coatedwith a non-reactive hydrophilic polymer. The coatings and coatedsubstrates are said to be useful for situations where they come intocontact with mucous membranes.

U.S. Pat. No. 5,026,607 describes the formation of a slippery coating ofa urethane and a silicone or siloxane emulsion. A crosslinking agent,such as a polyfunctional aziridine, may be added to crosslink carboxylfunctional groups in the coating with carboxyl functional groups on thesubstrate surface. The use of primers in the case of a PET substratesurface is also disclosed to effect better adhesion of the coating tothe substrate. Alternative treatment methods to the use of primers, forexample, the introduction of substrate surface functionality by means ofplasma treatment or corona discharge to obtain hydroxyl, carboxyl, oramino functionality are also mentioned.

U.S. Pat. Nos. 5,077,352 and 5,179,174 describe the formation oflubricious coatings applied to a variety of substrates by means offorming crosslinked polyurethanes in the presence of polyethylene oxidepolymers at high temperatures. No surface treatment of the substratesurfaces is described and the selection of the isocyanate compoundsincludes, in particular, reactive aromatic diisocyanates of the type notbelieved to be biocompatible. It is doubtful whether these methods canbe recommended for use with intravenous catheter devices in view of theknown carcinogenic nature of the amines which can result from thedecomposition of such polyurethane polymers. Moreover, the hightemperature polymerization procedures suggested can result inunacceptable physical changes of several of the polymeric materialsutilized in angioplasty catheters.

Similar drawbacks pertain to the methods and compositions described inU.S. Pat. No. 5,160,790 describing the use of the same type ofpolyurethane polymers with various PVP polymers as the hydrophilicpolymer species.

U.S. Pat. No. 5,132,108 discloses the use of plasma treatment of certainpolymeric substrate surfaces, to introduce carboxyl and/or hydroxylreactive groups thereon, utilizing an oxygen and water-containing plasmagas, followed by treating the resulting polymeric surface with a spacercomponent having amine groups. The treating step is conducted in thepresence of a coupling agent, whereby covalent linkages are formedbetween the spacer component amine groups and the reactive sites of amodified hydrophilic polymeric substrate surface. Finally, anantithrombogenic, fibrinolytic or thrombolytic agent, such as heparin orother polysaccharides is contacted with the spacer component-treatedmodified polymeric surface. This method utilizes the introduction ofrelatively slow reacting carboxyl and/or hydroxyl groups onto thesubstrate surface, and encompasses too many processing steps forcost-effective production of medical devices. Although the resultingcoated surfaces are biocompatible, they are not slippery and do not havelow coefficients of friction.

U.S. Pat. No. 5,112,736 describes a method of introducing aminofunctionality on a variety of polymeric substrate surfaces, includingpolymers of polypropylene (PP), polyethylene (PE), polyvinylchloride(PVC), and polyvinylidenefluoride (PVDF), by plasma-treatment thereof inthe presence of radiofrequency plasma discharge by means of ammonia,organic amine-containing gases, or mixtures of such plasma gases. Themethod is used for very hydrophobic hydrocarbon polymer articles such asPP membranes. It does not appear to give good results with PE polymers.PP films which contain amino groups on their surfaces are used for DNAsequencing on the membranes. No reference with respect to their use forattachment of hydrophilic PU polymers to highly hydrophobic substratesis made, nor does the reference disclose reliable methods to affix aminosurface groups to PE surfaces which would be expected to work in theproducts and processes contemplated by the present invention. Thedrastic influence of the chemical and physical composition of bodyfluids upon the permanence of low friction coatings when exposed todynamic forces in such liquids has heretofore not been recognized.Whereas many slip additives, such as relatively low molecular weightsilicones and a variety of hydrophilic polymers, exhibit slipperinessand relatively good permanence in the presence of water or salinesolutions, they quickly lose their efficacy by exposure to dynamicforces in the presence of blood, a much more complex fluid composition.

Accordingly, there remains a need in the art of medical devices for animproved slippery coating material that demonstrates wear permanence,combined with the characteristics of biocompatibility, low toxicity andlow coefficient of friction in contact with body fluids, especiallyblood.

SUMMARY OF THE INVENTION

The present invention encompasses cohesive, biocompatible, high watercontent, slippery polyurethane hydrogel coatings which are covalentlybonded to and tenaciously adhere to plasma-treated polymeric plastic orrubber substrates, or chemically-treated metallic substrates, such asare utilizable for medical devices, which satisfy all of the aboverequirements. The present invention encompasses the tenaciously adheringcoating compositions themselves, as well as materials composed ofpolymeric plastic, rubber or metal substrates coated with the coatingcompositions, and products fabricated from the coated materials,including, especially, coated medical devices such as catheters,catheter balloons and stents. The present invention also encompassesmethods for applying such protective, wear-resistant, tenaciouslyadhering and biocompatible slippery barrier coatings to polymericplastic or rubber substrates, and to metal substrates, particularly, tosubstrates for use in medical devices. The cohesively bonded,tenaciously adhering, slippery coating compositions and materials of thepresent invention are biocompatible, highly suited for use in contactwith blood, demonstrate a low coefficient of friction with body fluidsand a high degree of permanence when applied to a wide variety ofmedical devices in contact with various body fluids.

The method for applying the tenaciously adhering coatings of the presentinvention to polymeric plastic or rubber substrates, and to metalsubstrates, particularly for use in the fabrication of medical devices,generally consists of first plasma treating a polymeric plastic orrubber substrate or chemically-treating a metal substrate, to affixamine-containing groups, especially amino groups, onto its surfacelayers; next, applying a biocompatible intermediate hydrophilicpolyurethane coating, containing isocyanate groups, which form covalenturea bonds by reaction of the terminal isocyanate groups of the coatingintermediate with the previously formed amine-containing groups providedby the plasma treatment of the polymeric plastic or rubber substrate, orchemical treatment of a metal substrate, and which thereby becomeattached to the substrate, forming a "tie coat"; and, finally,converting the covalently bonded polyurethane tie coat into a hydrogelby exposure to and reaction with water or atmospheric moisture, therebyforming a protective, tenaciously adhering, hydrophilic, hydrogelcoating on the intermediate tie coat to lubricate the outer surface ofthe device or part thereof which comes in contact with body fluids. Thecovalently attached protective polyurethane hydrogel coating is slipperywhen wet and the coated surface exhibits excellent permanence and wearcharacteristics when exposed to dynamic forces in the presence ofvarious body fluids, especially blood. Furthermore, these coatingsgreatly enhance the biocompatibility of the resulting medical deviceduring use. The hydrogel coatings also include compositions whichcontain additional hydrophilic polymers and other lubricious ingredientsin addition to the hydrophilic polyurethane polymers.

It is known to those skilled in the art that surface treatment ofpolymeric surfaces by way of radio frequency plasma discharge conditionscan activate the polymeric surfaces with respect to the physical andchemical characteristics of the boundary layers. It is further knownthat various surface coatings of medical devices can enhance theslipperiness and biocompatibility of the medical apparatus when incontact with body fluids. In order to obtain excellent adhesion, goodstrength, permanence, and biocompatibility of the barrier coats, theirphysical and chemical characteristics are immensely important. To affixbarrier coats to various surfaces the use of polyurethane polymersand/or reactive isocyanate intermediates have often been suggested. Itis well known that the isocyanate derivatives from aromaticpolyisocyanates exhibit much greater reactivity or other interactionswith substrate boundary layers, for example due to surface moisture orsubstrate polarity, than do the slower reacting aliphatic orcycloaliphatic isocyanates containing NCO groups that exhibit often notonly appreciably lower rate of reaction, but also significant sterichindrance with regard to chemical interaction with active hydrogencompounds. The preferred isocyanate-derived hydrogels of the presentinvention are derived from aliphatic, cycloaliphatic, araliphatic,heterocyclic or aromatic polyisocyanates, most of which are known toyield urethane polymers possessing good biocompatibility and lowtoxicity. However, a predominant number of the latter polyisocyanatescontain NCO groups which exhibit much lower order of activity than thearomatic isocyanates. Consequently, it is necessary to modify thechemical nature of the substrate surfaces in a manner to obtainpractically immediate cohesive bonding of the boundary coatings to saidpolymer substrates.

To this end, it has been discovered that the affixation of amino groupsto a polymer or rubber substrate can be accomplished by plasma treatmentof the polymer or rubber substrate with a nitrogen-containing gas suchas ammonia, organic amines, nitrous oxide (amino plus hydroxyl groups),nitrogen, and mixtures of these gases. In the case of very hydrophobicplastic substrates, for example, various grades of polyethylenes, nylons11 and 12, and the like, we have discovered that optimal results areachieved by combinations of various oxidative chemical treatments oroxygen-containing plasma-treatments, to make the highly hydrophobicsurfaces more polar or hydrophilic, followed by plasma exposure tonitrogen-containing plasma gases, or to gaseous ammonia or low-boilingamines, or mixtures thereof, to affix much more reactive amino groupsonto the substrate surfaces. Although they are very hydrophobic,polypropylenes lend themselves more readily to plasma-treatment withnitrogen-containing gases because they contain a more labile hydrogenatom attached to a tertiary carbon in each repeating unit. Hence,suitable methods of amino group fixation are available for polyolefinpolymers or other very hydrophobic plastic substrates. Amino groups canbe affixed to a metal substrate by chemical treatment.

Amino groups can bring about instantaneous reaction of the substratesurface with any of the isocyanate derivatives contemplated in theinvention. However, the amino groups are particularly useful withrespect to improving reaction of the rather sluggish isocyanate speciesthat are attached to secondary or tertiary carbon atoms of manypolyisocyanates. After plasma exposure, or chemical treatment, of thepolymeric or metallic substrate, respectively, a coating solution havingbetween about 1% to about 20% solids, preferably between about 2% to 6%solids, of an isocyanate prepolymer containing free NCO groups, derivedfrom water-soluble hydrophilic polyether polyols and one or more ofaliphatic, cycloaliphatic, araliphatic, heterocyclic, and aromaticpolyisocyanates, is applied to the treated substrate surface, allowed todry, and the coatings are then converted to protective slippery,hydrophilic hydrogel layers upon the devices' surfaces by exposure toaqueous media or atmospheric moisture. If desired, the hydrogelformation can be catalyzed by procedures known in the art. Preferredpolyisocyanates contemplated for use in the present invention includealiphatic, cycloaliphatic, araliphatic and aromatic isocyanates,especially diisocyanates, as well as their prepolymer derivatives.

In a preferred embodiment, the protective Intermediate or tie coat is ahydrophilic polyurethane derived from a copolyether polyol of ethyleneand propylene oxides, and isocyanates containing aliphatically bound NCOgroups to optimize biocompatibility, since corresponding polyaminesresulting from hydrolysis or biodegradation of such polyurethanes are ingeneral biocompatible. Copolyethers facilitate handling of theprepolymer intermediates, since the preferred types are liquid at roomtemperature, thus presenting enhanced handling characteristics Incommercial practice. The preferred plasma gases are ammonia or mixturesof ammonia with organic amines to optimize formation of amino groups onthe substrate surface. The hydrogel formation which yields the desiredpolyurea hydrogel upon exposure to aqueous media can be conductedwithout a catalyst, or in the presence of catalysts such as Inorganicbases, low-boiling tertiary amines, or water soluble primary orsecondary polyamines that become part of the polyurea hydrogel polymer.

The coatings and the methods of the present invention are particularlywell suited to affix tenaciously adhering, hydrophilic coatings tosubstrates such as polyethylene terephthalate, block copolymers ofaliphatic polyethers and aromatic polyesters, block copolymers ofaliphatic polyethers and polyamides, polyamides, polyimides,polyurethanes, hydrocarbon polymers such as polyethylene andpolypropylene, synthetic hydrocarbon elastomers, and natural rubber.These polymeric substrates are the ones most often used in medicaldevices such as various types of catheters, and catheter devices forcoronary angioplasty, including balloons.

The methods of the present invention for covalently attaching thehydrophillic polyurethane coatings to plasma- or chemically-treatedsurfaces are particularly useful for the manufacture of medical devicessuch as catheters, catheter balloons, and the like, which have coatedsurfaces that are vastly superior for use In blood, in comparison withthe lubricious silicone coatings and/or other hydrophilic coatingspreviously commonly used. The wear performance upon dynamic exposure Inblood Is normally lost rather quickly by the coated medical devices ofthe prior art. In contrast thereto, the covalently bonded PU hydrogelcoatings of the present invention, when affixed to various medicaldevices In accordance with the methods set forth In the presentinvention, exhibit exceptional durability even after many test cycleswhen exposed to dynamic forces in blood. These unanticipatedobservations and results represent a decided advance of the state of theart in the field of slippery coatings for medical devices.

The methods for producing the tenaciously adhering, slippery hydrophiliccoatings of the present invention are based on the plasma treatment ofvarious polymeric substrates with nitrogen-containing plasma gases toaffix amino groups onto the substrate surface, or chemical treatment ofmetal substrates to affix reactive amino-siloxane groups onto thesurface of those substrates, coating the resulting reactive surface witha hydrophilic polyurethane polymer coating solution, therebyinstantaneously and covalently bonding the hydrophilic polymerpermanently to the substrate, and then exposing the coated surface towater to form the desired final polyurea hydrogel coating. The polyureahydrogel may additionally contain other lubricious polymers and/or slipadditives, if desired. The coating is dried, packaged and sterilizedbefore shipping the device to which it has been applied, and can bereactivated within one minute, or less, after immersion into aqueousfluids before clinical use. After reactivation the resulting hydrophilicpolyurea hydrogel coatings exhibit excellent slipperiness, flexibility,toughness, outstanding permanence against premature wear in body fluids,and good biocompatibility. The covalently bonded slipperypolyurethane-polyurea (PU/PUR) polymer hydrogens exhibit unusualendurance during the insertion of such medical devices in criticalapplications within body fluids having complex compositions. The coateddevices are eminently beneficial for use in angioplasty devices,including balloon catheters, and exhibit remarkable slipperiness andunusual resistance towards manipulation in the presence of blood.

DETAILED DESCRIPTION OF THE INVENTION

The tenaciously adhering, hydrophilic coating compositions of thepresent invention are particularly suitable for medical devices,including catheters, balloons for use in conjunction with catheters,guidewires, metal tubing, and other devices having operationalrequirements and properties that can be improved by attaching slipperycoatings to one or more surfaces of such devices which come in contactwith body fluids. In accordance with the invention, the coatings includehydrophilic polyurethane polymers which are tenaciously adhered to theorganic plastic or rubber polymer substrates or metal substrates fromwhich the medical devices are fabricated by cohesive bonding, and uponexposure thereof to water, cause the resulting hydrogel coatings to formhydrophilic lubricating films on the apparatus or functional componentsthereof. The slippery coatings are characterized by goodbiocompatibility and good permanence of adhesion when exposed to dynamicforces in typical body fluids, such as blood and other chemically andphysiologically complex fluid compositions.

The present invention also relates to a method for the production ofcoated medical devices by means of first exposing an uncoated polymericdevice or precursor for subsequent fabrication into a device, or aparison for subsequent blow-molding into a balloon for use inconjunction with a medical device, to a high frequency plasma withmicrowaves, or alternatively to a high frequency plasma combined withmagnetic field support, or chemically treating a metallic device, toyield the desired reactive surfaces bearing at least a substantialportion of reactant amino groups upon the substrate to be coated, whichgroups can combine instantly with the terminal isocyanate groups of theprepolymer intermediates deposited upon the reactively coated polymer ormetal substrate surfaces. Particularly useful starting prepolymerintermediates for coating onto the polymer or metal substrate surfacesaccording to the present invention include hydrophilic polyurethaneprepolymer intermediates derived from water-soluble polyether polyolsand organic polyisocyanates. Preferred polyisocyanates includealiphatic, cycloaliphatic, araliphatic, heterocyclic, and aromaticpolyisocyanates containing aliphatically attached terminal isocyanategroups. On account of the relatively slow reactivity of the isocyanategroups of this class, the plasma treatment of polymeric substrates orchemical treatment of metal substrates is conducted in a manner to yieldrapidly reacting amino groups as the major desirable active species thatis present on the boundary layer of the substrates. Therefore, theplasma treatment is carried out with plasma gases containing nitrogenatoms; and chemical treatment is carried out with amine group-containingcompounds.

Quite surprisingly, the surface geometry of the polymeric materials usedfor the manufacture of medical apparatus remains relatively unaffectedby plasma treatment. Furthermore, it has been established that if theplasma treatment parameters are followed carefully, the degree ofamine-containing group, especially amino group, fixation on the surfaceis such that the isocyanate-containing coating intermediates which aredeposited thereon do not crosslink prematurely before the hydrogelformation step is undertaken. These factors are of importance because itis believed that the slipperiness efficiency of the hydrogel issubstantially improved by conducting the polymer formation reaction insuch manner as to form hydrophilic polymer chains of substantial lengthand limited degree of crosslinking to optimize the mobility of therelatively elastic resultant molecular structure of the coating surfaceson which it is desired to achieve low coefficients of friction.Premature crosslinking or excessive crosslinking of the coatingssurfaces is believed to be detrimental to achieving improvedslipperiness due to maintaining a low coefficient of friction, loweringof dynamic drag forces, and preservation of high elasticity, which isknown to improve frictional wear.

Typical polymeric substrates often employed for the medical devices ofthe present invention include thermoplastic polyurethanes (TPU),polyesters such as polyethylene terephthalate (PET), nylon polymers suchas nylon-1 1 and nylon-12, block copolymers of polyether and polyesterpolymers (for example various HYTREL® block copolymers, available fromDuPONT), block copolymers of polyether polymers and polyamides (forexample, PEBAX® resin series, available from ATOCHEM), polyimides,polyolefins such as polyethylenes (PE) and polypropylenes (PP),synthetic rubbers thermoplastic hydrocarbon elastomers including SBR andEPDM (KRATON®, available from SHELL, and other similar commercialproducts from other sources), as well as natural rubber. For catheterapplications used in angioplasty, components made from TPU, PET, nylons11 and 12, HYTREL, PEBAX, and PE are preferred polymeric substrates. Forcatheter balloons used in coronary angioplasty preferred polymericsubstrates are PET, nylons and PE.

It is often advantageous to pretreat the polymeric substrate surfacebefore plasma treatment with polar or nonpolar organic solvents for aperiod of from about 15 seconds, or less, to longer than severalminutes, in order to remove any surface impurities such as lubricants,antioxidants, plasticization agents, release agents, and the like. Theseimpurities can originate from initial polymer manufacturing processes orfrom plastics forming techniques such as extrusion, injection-molding,blow-molding, and the like. Typical solvents which can be used for thispurpose include alcohols such as methanol, ethanol, isopropanol, and thelike; ketones such as acetone, methylethyl ketone, and the like;chlorinated hydrocarbons such as methylene chloride,1,1,1-trichloroethane, and the like; hydrocarbons such as pentanes,n-hexane, petroleum ethers, other cleaning spirits, and the like; etherssuch as diisopropyl ether, dioxane, tetrahydrofuran, and the like; andmixtures of the above. In the case of non-flammable cleaning solventsthe removal of surface impurities can be carried out by means of vapordegreasers, a procedure well known in the art. It is also within thescope of the present invention to utilize aqueous solutions of nonionic,anionic, and cationic surfactants as washing fluids, if desired,followed by rinsing with water or distilled water to remove surfaceimpurities that can interfere with the plasma treatment. Impurities onthe substrate surface which are not part of the polymer matrix candetract from the formation of direct cohesive bonds with the substrates.Likewise, metal substrates should be degreased with organic solvents orwashed with appropriate detergents or roughened mechanically, or treatedwith combinations of the above procedures, before application oforganosilane, especially aminosilane, primers.

The speed of formation of cohesive bonds upon the substrate surfacesdepends on the reactivity of the functional groups attached to apolymeric substrate surface by means of plasma treatment or to ametallic substrate surface by means of chemical treatment, as well asupon the rate of reaction of the terminal isocyanate groups that arepresent in the intermediate polymer coating affixed to the substrates.Fast reacting isocyanate groups that are attached directly to thearomatic ring structure can be made to form cohesive bonds with avariety of slower reacting functional groups that are present in thebase plastic or rubber of a polymer substrate, on the plasma-treatedsurface of a polymer substrate, or on the chemically-treated surface ofa metal substrate. Aromatic isocyanates and their derivatives can formcohesive bonds at from room temperature to 70° C., or higher, withreactive chemical functional groups such as hydroxyl, urethane, urea,amide, carboxyl, and carbonyl, that are either present in the originalsubstrate polymer, or which have been affixed to a polymeric plastic orrubber substrate by oxidative- or plasma-treatment to yield, forexample, hydroxyl or carboxyl groups; or which have been affixed to ametallic substrate surface by the chemical treatment thereof. Oftentimesnon-plasma treated plastic surfaces having NCO-reactant functionalcomponents as part of their polymer make-up, or having oxidizedsurfaces, or even surface moisture, can result in reasonably goodadhesion when exposed to aromatic polyisocyanates or derivativestherefrom. However, this procedure has been observed to give borderlineresults in the presence of most commercially available aliphatic, and inparticular cycloaliphatic and sterically hindered araliphaticdiisocyanates and their derivatives containing much slower reactingisocyanate groups. Furthermore, from the standpoint of toxicity and/orbiocompatibility, the use of polyurethanes derived from aromaticpolyisocyanates and their hydrolytic or biodegradation aromaticpolyamine by-products, is less desirable where the materials are inanatomical contact, because aromatic amines are potentially hazardouscarcinogens. In this respect, caution must be exercised when the outercoatings on medical devices are employed in intravenous application indirect contact with body fluids, such as blood. Certain aromaticpolyisocyanates have, however, been previously shown to bebiocompatible. The use of aliphatic, cycloaliphatic, araliphatic, andheterocyclic polyisocyanates and prepolymers thereof containing onlyaliphatically-bound terminal NCO groups is, however, much preferred,because of the appreciably lower risk with respect to toxicity of theirPU polymers, and in particular because of the known goodbiocompatibility of their polyamine degradation products.

Because of the considerably slower reactivity of the above mentionedaliphatically-bound, and oftentimes also sterically hindered isocyanategroups attached to the diisocyanates and derivatives thereof comprisingthe preferred embodiments of the present invention, it has been foundadvisable to plasma-treat the polymeric substrates used for the variousmedical devices encompassed by the present invention. Plasma treatmentmust be designed to affix primary and/or secondary amino groupspreferentially or at least partially, upon the polymer surfaces of thesubstrate. These amino groups react instantly with the isocyanate groupsof the prepolymer coatings intermediates, even before the coatingssolvents are evaporated. Hence, the plasma treatment must be conductedin the presence of plasma gases that yield amino groups as at least asubstantial portion of the functional groups affixed to the substratesurface. Plasma gases that can yield amino functionality must containnitrogen as part of their chemical composition. Therefore, the plasmatreatment is preferably carried out with plasma gases containingnitrogen atoms, such as ammonia, primary and secondary amines, nitrousoxide, nitrogen, other gases containing nitrogen moieties, and mixturesof such gaseous compounds. Ammonia and low molecular weight organicamines as well as mixtures thereof, being in the vapor state atrelatively low temperatures, are preferred plasma gases. In the case oftreatment of very hydrophobic substrate surfaces, for example, variouspolyethylene (PE) substrates, suitable conditions encompass firsttreating the substrate material with a plasma gas containing oxygen,either pure or in air or water vapor, or with a mixture of oxygen andone or more non-reducible gases, such as argon (Ar) and ammonia (NH₃),followed by a second treatment with either a nitrogen-containing plasmagas consisting of NH₃, low-boiling organic amines, or mixtures thereof,or simply an NH₃ -containing or NH₃ /low-boiling mine-containing gaseouspost-stream soon after plasma treatment with a non-nitrogen-containingplasma. The net effect of such combination treatments is to affix asubstantial portion of highly reactive amino groups into previouslyhighly hydrophobic substrate surfaces and to simultaneously render themmuch more hydrophilic, which facilitates their interaction with thehydrophilic PU prepolymer to be affixed to the substrate as the"tie-coat".

The plasma treatment process of the present invention is applicable totreating a wide variety of organic polymeric substrate surfaces. Many ofthem have already been mentioned hereinabove, and they generallyencompass thermoplastic materials, although it is within the scope ofthe present invention to utilize also thermosetting polymers assubstrate materials for construction for some of the devicescontemplated in the present invention. For example, it can beadvantageous to crosslink catheter balloons to make them lesssusceptible to "winging" during deflation. As pointed out above, thesubstrate can be conditioned by means of washing or degreasing withsolvents, or alternately by means of removing surface impurities withcationic, anionic, or nonionic surfactants followed by rinsing withwater and drying. According to the present invention, the substrate isthen exposed to a gaseous plasma containing nitrogen atoms. Preferredplasma gases include ammonia and/or organic amines, or mixtures thereof.Suitable organic amines are, by way of example, relatively low boilingprimary and secondary amines having a structure (I-IV): ##STR1## whereinR₁ and R₂ are monovalent hydrocarbon radicals having from 1 to about 8carbon atoms, preferably from 1 to about 4 carbon atoms; R³ is adivalent hydrocarbon radical having from 2 to about 8 carbon atoms,preferably from 2 to about 6 carbon atoms; and R₄ is hydrogen or a loweralkyl group.

Examples of suitable amines include methylamine, dimethylamine,ethylamine, diethylamine, methylethylamine, n-propylamine, allylamine,isopropylamine, n-butylamine, n-butylmethylamine, n-amylamine,n-hexylamine, 2-ethylhexylamine, ethylenediamine, 1,4-butanediamine,1,6-hexanediamine, cyclohexylamine, N-methylcyclohexylamine,ethyleneimine, and the like.

Methods for plasma treatment with various plasma gases or combinationsthereof are known in the art but generally lack the specificity demandedby the method employed in the present invention.

According to the present invention, for the case of ammonia and/ororganic amines, or mixtures thereof as the plasma gases, a radiofrequency (RF) of 13.56 MHz, with a generating power of from about 0.1Watts per square centimeter to about 0.5 Watts per square centimeter ofsurface area of the electrodes of the plasma apparatus is suitable. Theplasma treatment comprises first evacuating the plasma reaction chamberto a desired base pressure of from about 10 to about 50 m Torr. Afterthe chamber is stabilized to a desired working pressure, by flowingammonia and/or organic amine gases, or mixtures thereof through thechamber at rates of from about 50 to about 730 standard ml per minute,preferably from about 200 to about 650 standard ml per minute, and a gaspressure of from about 0.01 to about 0.5 Torr, preferably from about 0.2to about 0.4 Torr. A current at the desired allowed frequency and levelof power is supplied by means of electrodes from a suitable externalpower source. Power output is from 0 to about 500 Watts, preferably fromabout 100 to about 400 Watts. The temperature of the plasma chamber isgenerally from about room temperature to about 50° C., and the treatmentis usually carried out for a time of from about 30 seconds to about 10minutes. The plasma chamber is initially at room temperature, however,during plasma treatment, the temperature in the chamber rises to atemperature not exceeding 60° C., due to molecular collisions. Theplasma treatment can be performed by means of a continuous or batchprocess.

In the case of batch plasma treatment, the plasma surface treatmentsystem known as PLASMA SCIENCE PS 0350 was utilized (HIMONT/PLASMASCIENCE, Foster City, Calif.). The system is equipped with a reactorchamber, an RF solid-state generator operating at 13.56 MHz capable ofoperating at from 0 to 500 watts power output, a microprocessor controlsystem, and a complete vacuum pump package. The reaction chambercontains an unimpeded work volume of 16.75 inches in height, by 13.5inches in width, by 17.5 inches in depth. For the application of theammonia plasma, organic amine plasma, or a mixture of such plasma gases,the equipment is operated at a power output of from about 50 to about400 Watts, a gas flow rate of from about 50 to about 730 standard ml/minfor a time period of from about 15 seconds, up to about 10 minutes,under a vacuum, and at temperatures of from room temperature to about50° C. A preferred range is from about 60 to about 120 Watts and anammonia, organic amine or mixed gas flow rate of from about 700 to about730 standard ml/min, a vacuum from 0.01 to 0.5 Torr, at a temperature offrom about 30° C. to about 50° C., for a period of from about 15 secondsto about 3 minutes.

In order to define conditions for high permanence of adhesion of thehydrogel coatings, as well as the optimized degree of slipperiness andpermanence in blood, a highly preferred method of operation consists ofoperating at a power range of from about 100 to about 400 Watts, anammonia flow rate of about 200 to about 650 standard ml/min, a vacuum offrom about 0.1 to 0.5 Torr, a treatment temperature of about 25° C. toabout 40° C., and an exposure time of from about 30 seconds to about 3minutes. Optimization procedures for the plasma treatment and theperformance of the covalently bonded, tenaciously adhering, hydrophilicpolyurethane hydrogel coatings can be determined on the basis ofevaluation of dynamic drag forces versus exposure cycles and endurancein blood. Similar preferred conditions are utilized for nitrous oxideand nitrogen, or other gas mixtures containing nitrogen moieties asplasma gases.

Polymeric substrates which contain auxiliary chemicals such asantioxidants, ultraviolet and other light stabilizers, catalyst residuesfrom their manufacture, organic and inorganic fillers such as calciumcarbonates, clays, barium sulfate used as the radiopaque filler formedical devices, carbon blacks and other pigments, and the like, arealso suitable as substrates for plasma treatment in accordance with themethods of the present invention.

The plasma treatment procedures of the present invention have been foundto fade very slowly over a period of months. It is not certain whetherthis is associated with oxidative degradation of the functional groupsattached to the substrate surfaces, or some other gradual decayprocesses. A preferred practice consists of coating the medical devicewithin two months, or less, after the plasma treatment of the substratematerial from which the device is fabricated has taken place. The highlypreferred method consists of coating the plasma treated medical deviceswithin two weeks, or less, after plasma treatment of the substratematerial with the ammonia or organic amine plasma gases, or mixturesthereof.

Where the substrate to be coated is a metal, chemical treatment of thesubstrate surface with organosilane compounds having reactive aminoalkylmoieties that are attached to the silicone molecule to affix reactiveamino-silane groups thereto must first be performed. Such aminosilaneshydrolyze rapidly in water and the resulting silanols can react andcondense with reactive species of the metal surface to form quite stablecohesive ancher bonds therewith. The amino ends of the hydrolyzed andcondensed aminosilane are available for reaction with functional groups,such as isocyanate groups of the prepolymer coating intermediate of thepresent invention. The aminosilane primer treatment of the metalsurface, therefore, produces a similar effect as the plasma treatment ofpolymer substrates. Typical metal substrates, suitable for use inmedical devices, which may be chemically treated include stainless steeland titanium, and metal alloys of steel, nickel, titanium, molybdenum,cobalt, and chromium, and other metals, such as the alloys, nitinol(nickel-titanium alloy), and vitallium (cobalt-chromium alloy). It isgenerally also recommended that the metal substrate surface bepre-treated by washing with a solvent to remove dirt and grease so thatthe silane groups may better attach themselves to the metal substratesurface. The amino and silane groups are connected by an intermediatehydrocarbon chain. The amino groups are outwardly terminal and are freeto react with and covalently bond with free terminal isocyanate groupsin the subsequently applied hydrophilic polyurethane pre-polymerintermediate coating. The length of the intervening hydrocarbon chainbetween the silane group and the amino groups can be tailored to thesituation. Typically, the intermediate chain is a simple lower alkylchain (i.e., (--CH₂ --)_(x), where x is from 2 to 8).

Typical aminosilanes which are suitable for priming the metal surfacesof the devices contemplated by the present invention include, by way ofexample, γ-aminopropyltriethoxysilane (A-1100; Union Carbide), anaqueous prehydrolyzed aminoalkyl silanol solution (A-1106 is aprehydrolyzed aminoalkylsilanol, prepared from aminosilane A-1100),γ-aminopropyltrimethoxy-silane (A-1110),β-aminoethyl-γ-aminopropyltrimethoxysilane (A-1120), and the like.Typical aqueous aminosilane priming compositions contain from about0.5%, by weight, to about 3% by weight, of the aminosilane compound inwater. After applying the hydrolyzed aminosilanes to the metal device bydip-coating or other means, water and alcohols from hydrolysis areremoved by evaporation, and the primed surface is coated with ahydrophilic PU urethane adduct intermediate of the present invention toform the resulting covalently attached PU/UREA tie-layer on the metalsurface. The tie-layer is then converted to the final hydrogel by theinfluence of moisture or aqueous medium.

According to the present invention isocyanate prepolymers which may beused for the preparation of the hydrophilic polyurethane coatingintermediates comprise prepolymer reaction products of water-solublemono- or polyfunctional polyethers, random copolyethers, and blockcopolyethers from 1,2-alkylene oxide and alternatively copolyethers from1,2-alkylene oxides and tetrahydrofurane or tetrahydropyrane withorganic polyisocyanates selected from the group consisting of aliphatic,cycloaliphatic, araliphatic, and heterocyclic polyisocyanates, andderivatives thereof. Preferred polyethers employed as starting materialsfor such isocyanate prepolymer adduct intermediates includewater-soluble homopolyethers of ethylene oxide, copolyethers of ethyleneand propylene oxides, copolyethers of ethylene and 1,2-butylene oxides,copolyethers from mixtures of all the above 1,2-alkylene oxides, andcopolyethers of ethylene oxide and tetrahydrofurane. Highly preferredcopolyethers are homopolyethers of ethylene oxide, and copolyethers fromabout 70% to about 85%, by weight, of ethylene oxide and from about 15%to about 30%, by weight, of propylene oxide. Copolyethers containing asmuch as from about 17.5% to about 30%, by weight, of propylene oxide areparticularly preferred because they are liquid at room temperature,which greatly facilitates the handling of the resulting prepolymeradducts, and because they also remain liquid at temperatures appreciablybelow room temperature. The moderate levels of propylene oxide do notdetract from the solubility of the resulting copolyethers in water, andthe hydrophilicity of the final hydrogels makes them particularlysuitable for the manufacture of lubricious wear-resistant hydrogelcoatings.

Very surprisingly, it has also been found that monofunctionalwater-soluble polyether alcohols from ethylene oxide, as well asmonofunctional copolyether alcohols from ethylene oxide and propyleneoxide, containing a propylene oxide level of from about 15% to about30%, by weight, are also well suited for the purpose of preparingisocyanate prepolymer intermediates for the preparation of lubricioushydrogels employed as top coats for medical devices. Furthermore, it hasalso been confirmed that admixtures of hydrogels comprising poly- andmonofunctional polyether and/or copolyether isocyanate prepolymers asthe base intermediates for hydrogel formation result in coatingsexhibiting surprisingly superior lubricity and adhesive permanence whentested in body fluids, such as blood. Moreover, it has been discoveredthat the isocyanate prepolymers can be made in a single step byconducting the isocyanate prepolymer formation from mixtures of mono-and poly-functional polyethers. Furthermore, it is also feasible toconduct the prepolymer preparation by sequential addition of themonofunctional polyether to the isocyanate-terminated prepolymer fromthe polyfunctional polyether polyol. Consequently, the combinationsconsisting of prepolymers of water-soluble polyfunctional andmonofunctional polyethers or copolyethers, and polyisocyanates selectedfrom the group of aliphatic, cycloaliphatic, araliphatic, and aromaticdiisocyanates, and derivatives thereof, are still other preferredembodiments of intermediate coatings of the present invention used forthe manufacture of tenaciously adhering, hydrophilic hydrogel coatings.

Methods for the manufacture of such water-soluble polyfunctionalhomopolyethers, random copolyethers and block copolyether polyols, aswell as monofunctional homopolyether and copolyether alcohols, are wellknown in the art. Typically, monofunctional polyether alcohols andpolyfunctional polyether polyols are derived by the addition of1,2-alkylene oxides to monohydric or dihydric alcohols or phenols, orpolyhydric alcohols or phenols in the presence of alkaline catalysts.Copolyether diols from ethylene oxide and tetrahydrofurane or largerring cyclic oxides are generally made in the presence of Lewis acids asthe catalysts, as is well known in the art. Representativemonofunctional and polyfunctional starters for the 1,2-alkoxylationreactions are, by way of example, methanol, ethanol, isopropanol,butanol, amyl alcohols, hexanol, 2-ethylhexanol, lauryl alcohols andother fatty alcohols, phenol, cresols, higher alkyl phenols, naphthols,and the like; water, ethylene glycol, diethylene glycol, propyleneglycol, dipropylene glycol, 1,4-butanediol, 1,6-hexanediol, neopentyleneglycol, resorcinol, hydroquinone, bisphenol A, xylenols, glycerol,trimethylolpropane, pentaerythrtol, α-methyl glucoside, sorbitol,sucrose and the like. Lower carbon monofunctional alcohols are generallypreferred starters for monofunctional polyethers and copolyethers. Waterand lower carbon aliphatic glycols are preferred for difunctionalpolyether and copolyether diols. Glycerol and trimethylpropane arehighly preferred for the manufacture of trifunctional polyether andcopolyether polyol intermediates.

The monofunctional and polyfunctional hydroxyl-terminated polyethers andcopolyethers, especially polyether and copolyether alcohols and polyols,used as starting materials for the manufacture of hydrophilic isocyanateprepolymers of the present invention have equivalent weights (EW) perhydroxyl in the range of from less than about 500, to greater than about20,000. Within this general range, preferred EW's for monofunctionalpolyether alcohols and copolyether alcohols are from about 2,000 toabout 10,000, and highly preferred values range from about 3,500 toabout 6,000. Further within the above broad ranges, preferred EW rangesfor the glycerol and trimethylolpropane 1,2-alkylene oxide adducts arefrom less than about 1,500, to greater than about 7,500, while the mostpreferred EW ranges for these trifunctional products are from about1,500 to about 2,500. With respect to difunctional polyether diol andcopolyether diol adducts, preferred EW values range from about 750 toabout 5,000, and a highly preferred range is from about 1,000 to about4,000. The EW values of these polyether alcohols and polyols can bedetermined by phthalation or acetylation of the hydroxyl group by wellknown analytical techniques such as, for example, ASTM Method D-4274-88.

As is well known, the above-described polyether adducts from1,2-alkylene oxides are normally prepared by means of base catalyzedoxide addition to mono- and polyhydric alcohols or phenols. Typicaloxyalkylation catalysts are hydroxides and alkoxides of alkaline earthmetals such as sodium and particularly potassium. Representative of suchcatalysts are potassium and sodium hydroxide for the manufacture ofpolyfunctional polyethers, and sodium and potassium alkoxides of lowermonohydric alcohols and phenols such as the methoxides, ethoxides,phenoxides, and the like, when the desired polyethers are intended to bemonofunctional. Such catalysts are generally used at levels of fromabout 0.05% to greater than about 0.3%, by weight, based upon the oxideadducts being made. However, catalyst residues must be removed prior tothe reactions with polyisocyanates, because they will catalyzeunattractive side reactions of isocyanates, such as trimerization anddimerization of isocyanates, or formation of allophantes from urethanesformed during the prepolymer step, formation of urea and biuretderivatives, or additional undesirable byproducts. Consequently, theymust be removed by way of ion exchange reactions or other means afterthe oxyalkylation step. Similarly, if the polymerization is performedwith acidic catalysts such as Lewis acids, they must also be removed byknown methods, because they will slow down the reaction of theisocyanate group with hydroxyl-terminated polyethers. The presence ofundesired alkali metals can also be examined by well establishedanalytical procedures (ASTM D-4668-87). In this regard, the totalpresence of sodium and potassium metals in the polyethers should bewithin the range of from 0 to 10 ppm, preferably less than about 5 ppm,to avoid complications during the prepolymer reaction step.

Furthermore, it is important that the hydroxyl-containing hydrophilicpolyethers contain very low levels of water prior to their reaction withpolyisocyanates to form the corresponding prepolymers. Moisture can leadto urea group formation and subsequent gelation of such prepolymers bymeans of biuret crosslinking reactions which interferes with thesubsequent coatings steps. Consequently, it is advisable to dry suchpolyethers by means of azeotropic distillation with aromatichydrocarbons such as toluene or xylenes, by careful drying under vacuumat 1000 to 120° C. at pressures of from less than about 5 to about 10torr, or by combinations of azeotropic distillation and vacuum drying.These procedures are well known in the art.

After removal of catalysts, the resulting polyether alcohols orpolyether polyols must be protected from oxidation in the presence ofair by means of antioxidants. Most of the antioxidants used incommercial practice are not biocompatible and are not useful forapplications involving medical devices of the type employed for clinicaluse in body fluids. On account of the relatively short insertion timesof the medical devices of the present invention, certain antioxidantssuch as IRGANOX 1010, IRGANOX 1076 (CIBA-GEIGY), SANTONOX R (MONSANTO),and similar compounds can be considered to be acceptable for short usein the bloodstream, since they have exhibited a low order of toxicity inother applications. The antioxidant level is generally at from about0.01% to about 0.05%, by weight, based on the hydroxyl-terminatedpolyether intermediate.

Suitable polyisocyanates for the manufacture of the hydrophilicpolyether and copolyether prepolymer intermediates of the presentinvention include aliphatic, cycloaliphatic, araliphatic, heterocyclicand aromatic polyisocyanates of the type described by W. Siefken inAnnalen der Chemie, Volume 362, pages 75-136, and in many otherpublications well known in the art. Preferred polyisocyanates includethe commercially available diisocyanates such as 1,4-tetramethylenediisocyanate, 1,6-hexamethylene diisocyanate (HDI), trifunctional biuretand isocyanurate derivatives of HDI (MILES CORPORATION, PolymersDivision; OLIN CORPORATION, Olin Chemicals), isophorone diisocyanate(IPDI), the isomer mixtures of methylene bis(4-cyclohexylenediisocyanates) known as DESMODUR W® (MILES CORPORATION, PolymerDivision), m-xylylene diisocyanate, p-xylylene diisocyanate,m-tetramethylxylylene diisocyanate known as TMXDI-meta® (CYTECINDUSTRIES, Inc., Stamford, Conn.), p-tetramethylxylylene diisocyanate,the isomer mixture of bis(isocyanatomethyl)1,3-cyclohexylene (MITSUBISHIGAS CHEMICAL CO., Inc., Toyko, Japan), and trans 1,4-cyclohexylenediisocyanate. A number of the above-described di- and poly-isocyanatesare commercially available. Most of them are known to yieldbiocompatible polyurethane polymers, since they are known to yield aminehydrolysis products which are known to exhibit very low toxicity. Thishas been demonstrated in the case of HDI, IPDI, DESMODUR W®, and isexpected to be valid for TMXDI and other commercially availablediisocyanates. Preferred polyisocyanates for the purpose of the presentinvention include aliphatic, cycloaliphatic, araliphatic and aromaticisocyanates. Particularly preferred polyisocyanates include1,6-hexamethylene diisocyanate, and especially its trifunctionalisocyanurate and biuret derivatives, all of which exhibit low toxicity,isophorone diisocyanate and its trifunctional isocyanurate derivatives,DESMODUR W®, and TMXDI-meta®.

For the purpose of the present invention, the polyether and copolyetherprepolymer adducts prepared from the above described polyethers arepreferably reacted with about two equivalents of the isocyanatecomponent per equivalent of the polyether hydroxyl compound to reactmost, if not all, of the hydroxyl groups which are available forconversion to the corresponding urethane polymer. In addition, it isalso feasible to utilize the above diisocyanates as chain-extensionagents to increase the chain length of difunctional prepolymers derivedfrom polyether diols or copolyether diols. In this case, the relativeratio of the reactants is adjusted accordingly to compensate for thechain lengthening action. In most cases the aliphatically attachedisocyanate groups are either sterically hindered, attached to secondarycarbon atoms (═CH--NCO) or tertiary carbon atoms [--C(CH₃)₂ --NCO], forexample, such as in TMXDI, all of them contributing sufficiently to slowdown the prepolymer formation sufficiently as to necessitate the use ofisocyanate catalysts for the formation of the prepolymers. With a fewsomewhat faster reacting polyisocyanates, such as for example, HDI andits derivatives, other straight-chain, non-hindered alkylenediisocyantes, or m- and p-xylylene diisocyanates, the prepolymer adductreaction can be conducted without a catalyst, if desired. However, evenwith these materials the catalytic prepolymer process is usually morecost effective.

With the possible exception of m- and p- TMXDI which are only moderatelytoxic as the free diisocyanate, in all other cases it is prudent toconduct the prepolymer formation is such manner as to minimize thepresence of unreacted free diisocyanate. This is feasible by judiciousselection of the NCO/OH reactant ratios and/or selection of theappropriate catalysts and catalyst levels during the formation of theprepolymers. Furthermore, it is also feasible to remove unreacted freediisocyanates by means of thin-film evaporators, a procedure well knownin this art. In the case of the highly hindered and slow reactingdiisocyanates the use of the catalysts is definitely recommended and is,in fact, often essential to react substantially all the hydroxyl groupsof the starting polyethers polyol intermediates.

The isocyanate reaction for the formation of prepolymers fromhydroxyl-containing polyethers can be catalyzed by means of tertiaryamines, or many metal catalysts, as is well known in the art. Althoughtertiary amines are very desirable catalysts for the formation of thePU/PUR hydrogel polymers and copolymers from the PU prepolymers of thepresent invention, they are not particularly useful for the manufactureof the NCO-terminated PU prepolymers because they can accelerateundesirable side reactions, for example, trimerization of free NCOgroups which can lead to premature gelation of such prepolymers. Theselection of appropriate metal catalysts is also difficult because manyof them can also cause trimerization, or are too toxic for use in themedical devices of the present invention. On account of their highcatalyst activity, high selectivity with respect to the hydroxylreaction, and favorable cytotoxicity when used at low concentrations,tin compounds are highly preferred catalysts. Tin catalysts, such asstannous acylates, and dialkyltin compounds, such as dialkyltindiacylates and dialkyltin oxides, are known to be highly effective invery small concentrations. Because they are not known to catalyzetrimerization reactions of isocyanates and they are powerful catalystsfor the hydroxyl-isocyanate reaction, they are expected to besatisfactory for the intended uses of the devices contemplated by thepresent invention. In this respect commercially available compounds suchas stannous octoate, stannous oleate, dibutyltin dilaurate, dimethyltindilaurate, dioctyltin oxide, and other similar tin compounds are knownto be biocompatible when used in moderate amounts. Furthermore, catalystlevels should be kept as low as possible to avoid any side reactions.Typical catalyst concentrations for tin compounds are from 5 to about300 parts per million (ppm), preferably from about 10 to about 50 ppm,and most preferably, from about 10 to about 20 ppm. In the case of HDIand its derivatives the rates of reaction are sufficiently high to avoidthe use of catalysts for the prepolymer formation altogether, ifdesired. Moreover, it is highly advisable to remove unreacted HDI bymeans of thin-film evaporation to avoid toxic work environments.Reaction times when using catalysts are from about 2 hours to not morethan about 6 hours.

Reaction temperatures for the prepolymer formation can vary from roomtemperature up to as high as about 85° C. to 90° C., with a preferredreaction temperature being from about 50° C. to 70° C. For the purposeof achieving good shelf stability of the prepolymer intermediates, theuse of the lowest practical catalyst level is generally preferable. Itis often possible to have satisfactory shelf lives for such prepolymersof from about 4 to about 6 months, or more, when they are stored nearroom temperature or somewhat below. Recent publications with respect tothe catalysis of isocyanates of interest for the purpose of the presentinvention have been published in Modem Paint and Coatings, June, 1987(E. P. Schiller and J. Rosthauser, MOBAY CORP.), and by K. Hatada etal., Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 28,3019-3027 (1990) [Reactions of isophorone diisocyanate with amine andtin catalysts].

The progress of the isocyanate reaction can be followed by measuring thedisappearance of the hydroxyl groups by means of infrared techniques, ormore accurately, by analysis for NCO content (ASTM D-4666-87). Thereaction can be discontinued when substantially all hydroxyls havereacted, or when the expected calculated % NCO content, or a level nearthat value has been attained. The reaction duration depends upon thecatalyst type and concentration, the nature of the ingredients and thereaction temperature, and can be defined quite precisely for particularcombinations of reactants. In any event, even at very low metal catalystlevels, it is feasible to achieve conditions that can complete thereactions within from as low as 3 to about 12 hours, at temperaturesranging from about 50° C. to about 80° C. A preferred reactiontemperature range is from about 50° C. to about 70° C. If HDI isutilized without a catalyst, similar reaction parameters apply.

It is within the scope of the present invention to conduct theprepolymer formation in the presence of suitable solvents to facilitatehandling of process ingredients, moderate the exothermic reactionprocesses, as well as to obtain solutions of the prepolymers beforemaking up the final coating compositions that involve the same or othersolvents than the ones utilized in the reaction step. The use ofmoderate amounts of solvents during prepolymer formation is a preferredoperating procedure because the resulting intermediates exhibit lowerviscosities and better handling and storage characteristics. For thepurpose of achieving suitable reaction conditions during the prepolymerformation step, the total solids content of the reactants utilized inthe prepolymer synthesis can vary over a wide range, for example fromabout 20%, by weight, to as high as about 80%, by weight. A preferredrange is from about 30%, by weight, to about 70%, by weight, and a mostpreferred range is from about 40%, by weight, to about 60%, by weight.The solvents which are utilized in the prepolymer process should be freeof water ("urethane-grade" solvents), and non-reactive with theisocyanates used in the process. Such solvents or often commerciallyavailable or can be dried suitably by means of molecular sieves, aprocedure well known in the polyurethane art.

The solvents should preferably have a boiling point above the reactiontemperature utilized for the prepolymer formation, but should boil lowenough to allow convenient evaporation of the diluents after thesubsequent coating operation of the plasma-treated substrate material ofthe medical device or other object. Furthermore, the solvents should notbe detrimental to the materials of construction used as the substratematerial of the medical devices during the subsequent coatingoperations. Typical solvents which are useful for the preparation of theisocyanate prepolymers of the present invention include those in whichboth the polyisocyanates as well as the hydrophilic polyethers aresoluble, to afford homogenous reaction. Aromatic hydrocarbon solventssuch as benzene, toluene, xylenes, and the like, ketones such asmethylethyl ketone, ethers such as methyl tert. butyl ether,tetrahydrofurane, dioxane, esters such as methylethoxy acetate,methylisopropoxy acetate, ethyl acetate, butyl acetate, ethyl formate,chloroalkanes such as 1,1,1-trichloroethane, and mixtures of thesesolvents, are among the media useful for the preparation of thehydrophilic prepolymers of the present invention. Solvents which can beadmixed after the prepolymer formation to make up the final coatingsolution can also include lower boiling solvents such as pentanes,hexanes, methylene dichloride, acetone, and other low boiling solventsthat can speed up the process of evaporation after coating of theplasma-treated substrate material.

In accordance with the present invention the initial coating step of theplasma-treated substrate with the solution of the original prepolymerintermediate can be performed at a solids content of from about 1%, byweight, to about 20%, by weight, or higher, based upon the total weightof the prepolymer and the solvent. A preferred solids content is fromabout 1.5%, by weight, to about 8%, by weight, and a most preferredcoating solution has a solids content of from about 1.5%, by weight, toabout 4%, by weight, based upon the coating composition. The coatingprocess can be performed by means of dip-coating, continuous coating bymechanically pushing or pulling the device through a coating trough, oralternatively by means of spray coating. The amount of coating solutionto be deposited upon the device is determined by means of the variousprocess parameters including the measurement of lubricity and durabilityof the finished hydrogel coating deposited upon the functional device.In the case of dip coating or traverse coating through a trough, thecoating contact time can vary from a few seconds to as long as 1 minute,or more. The efficacy of the coatings depth, even at thicknesses of fromless than about 1 mil about to 3 mils, has been found to be sufficientto achieve the desired objectives of excellent lubricity and permanence.In the event that the coating thickness becomes excessive, for exampleat from greater than about 5 mils, there exist the dangers of limitingthe wear properties of the coated medical device and of causing theflaking off of portions of the coating.

In accordance with the present invention the lubricious polyurethanehydrogel surface coating deposited upon the plasma-treated substrate isgenerally formed by means of two consecutive steps. The first stepinvolves applying the prepolymer coating intermediate, dissolved in oneor more suitable solvents described above, and then allowing thesolvents to evaporate. During this coating step, at least some of thefree NCO groups present in the prepolymer coating solution reactinstantaneously with amino groups which are affixed to the substratesurface and form covalent cohesive urea (UR) bonds with the modifiedreactive "tie-coat" surface. This occurs even before the solvents havebegun to evaporate. After removal of all, or almost all of the solvent,the next step includes exposing the remaining free NCO groups of thehydrophilic prepolymer intermediate to atmospheric moisture or to waterby such means as dip coating or other techniques to form the finaltenaciously adhering, hydrophilic, slippery polyurethane-polyurea(PU/PUR) hydrogel coatings.

One essential feature in all of the embodiments of the present inventionis the use of a base "tie-coat", deposited onto a plasma-orchemically-treated substrate, and having at least a substantial portionof functional surface groups in the form of amino groups capable ofreacting essentially instantly with the relatively slow reactingisocyanate end-groups of the hydrophilic polyurethane prepolymers ofwater-soluble polyethers and aliphatic, cycloaliphatic, araliphatic, orheterocyclic polyisocyanates or derivatives thereof, which become thecovalently bonded cohesive hydrophilic polyurethane-urea (PU/UR)"tie-coats" attached to the substrate. These "tie-coats" can beconverted to the desired polyurethane-polyurea (PU/PUR) hydrogels by theinfluence of aqueous media, or a mixed or double-coated blend thereofcomprising additional hydrophilic PU hydrogel prepolymers having theoriginal or different compositions can also be treated with water tocopolymerize the PU/UR "tie-coats" with the additional PU prepolymers toform the final lubricious polyurethane-polyurea (PU/PUR) hydrogelcopolymer coating compositions.

The covalently bonded PU/PUR hydrogel coating or covalently bondedcopolymer PU/PUR hydrogel coating of the present invention has a watercontent of at least 70% of the weight of the hydrogel coating(s), andpreferably a water content of from about 85% to about 90%, by weight, ofthe hydrogel coating(s). Such PU/PUR hydrogel polymer or copolymerPU/PUR hydrogel coatings can contain water in excess of 95%, by weight,based upon the dry hydrophilic hydrogel polymer(s) and yet maintainproperties of uniformity, elasticity and stability. The PU/PUR hydrogelcoatings or PU/PUR copolymer hydrogel coatings are extremely stable overtime, however, for practical purposes, it is more convenient to convertthe hydrogel to a dry, reactivateable form so that medical devices whichhave been coated with the lubricous coatings according to the presentinvention can be easily packaged using conventional dry, sterilepackaging techniques. The resulting dry, reactivateable outer hydrogelcoat is instantly reactivateable at the time of use of the device byimmersing the device in an aqueous medium.

The final step of hydrogel formation can be conducted in the absence ofa catalyst, or also in the presence of a suitable catalyst, if desired,to accelerate the reaction of water in liquid or vapor form with thefree isocyanate remaining after the first coatings sequence, ordouble-coating sequence of the various NCO-reactive prepolymerintermediates. The ensuing water reaction forms interconnecting ureagroups to form the long hydrogel polymer chains whose exact polymermacro- and micro-domains determine the lubricity and permanence of theresulting coatings. It is further feasible to conduct the hydrogelformation in the presence of instantly reacting water-soluble aliphatic,cycloaliphatic, araliphatic, heterocyclic, or still other diamines, toform the chain-extended hydrogels. Inorganic diamine derivatives such ashydrazine or substituted hydrazines containing active hydrogens on thenitrogen atoms are suitable chain-extenders. Such diamines are usuallydissolved in the aqueous phase, followed by dip coating, spraying, orsimilar techniques to rapidly convert the coating to the desiredhydrogel.

As pointed out above, the second step of the coatings method comprisestransformation of the initially formed and partially covalently bondedhydrophilic PU/UR isocyanate prepolymer intermediate that was depositedonto the substrate during the first step, into the final polyurethanehydrogel polymer by the action of water, either in the form of anaqueous coatings solution by means of dipping, spraying, and othermethods, or by exposing the coated substrate to atmospheric moisture.Other process options and embodiments have also been described above.The hydrogel formation can be conducted in the absence of a catalyst, inthe presence of a catalyst, or also in the presence of an amine chainextender that can function as a reactive ingredient for rapidlengthening of the polymer chains and simultaneously as a catalyst tospeed up the hydrogel formation. It is also feasible to perform thehydrogel synthesis in the presence of both, a catalyst and an aminechain extender, or also with an amine chain extender alone in theabsence of another catalyst. A still further alternative consists ofperforming the hydrogel formation by means of compounds containing acatalytic moiety, as well as an isocyanate reactant group such as, forexample, N,N-dimethylalkanolamines, amines which contain both, tertiaryamine groups as well as reacting primary or secondary amine groups. Itis also within the scope of the present invention to utilize mixtures ofthe above identified catalysts and any of the reactant catalyst species.

Preferred catalyst for the formation of the hydrogel polymers compriselow boiling tertiary amines such as trimethylamine, triethylamine,diethylmethylamine, tripropylamine, triisopropylamine, or otherlow-boiling amines that can be removed readily by drying of the finishedhydrogel coating. The low-boiling tertiary amine catalysts can beemployed as aqueous solutions wherein the medical devices are submergedafter the coating operation, or they can be admixed in suitableconcentration with a moist stream of air that contacts the hydrophilicprepolymer coating after evaporation of the coating solvent. The highlypreferred catalyst/chain extender is ethylenediamine, which is bestdissolved in water for dip-coating the medical device therein. Typicalcatalyst concentrations of the amine catalysts in water are from as lowas 0.03%, by weight, to as much as 0.3%, by weight, or higher. Preferredlevels for ethylenediamine are in the range of from 0.05%, by weight, toabout 0.15%, by weight. In the case of hydrogel formation by means ofmoist vapors contacting the prepolymer coated substrate, the catalystconcentrations are held near the lower levels to provide safer handlingcharacteristics. It is also feasible to recirculate catalyst-containingmoisture streams to sidestep excessive catalyst removal and/or recoveryproblems. With this catalyst technique it is generally feasible toreduce cure times for hydrogel formation to about 6 to 8 hours, or inmost instances even considerably less. The hydrogel formation is alsoaccelerated by increasing the exposure temperature above roomtemperature, for example from about 25° C., to as high as about 70° C.

However, it is also within the scope of the present invention to utilizehigher boiling tertiary amines that can be applied as aqueous solutionsto accelerate the water/isocyanate reaction by means of the typicalamine catalysts well appreciated by those skilled in the polyurethaneart. The disadvantage of utilizing high boiling amines, which are oftentoxic or irritants, is the requirement to remove them from the curedhydrogel by time-consuming methods such as rinsing with water.

In the case of non-catalyzed processing, the coated devices are exposedto atmospheric moisture, preferably at 50% relative humidity, or higher,for a period of from 6 hours, or longer, at temperatures ranging fromroom temperature to as high as 80° C. At the higher temperature rangescure time is about 6 hours, or longer, while at room temperature andrelatively low humidity cure times of as long as from about 24 hours toabout 72 hours are often required to obtain consistent results.

In the absence of basic catalysts the hydrogel formation normally takesfrom 24 to 48 hours, or more, to attain reliable cure rates with slowreacting NCO end groups. Besides organic amine catalysts and/or aminechain extenders, it is also feasible to conduct the hydrogel formationin the presence of moderately basic inorganic salts which can be removedfrom the cured hydrogel by means of adequate flushing with water.However, this procedure can be more expensive on account of more complexprocessing. Nevertheless, typical aqueous solutions containing inorganicsalts that are suitable to cure such hydrogels Include, among others,sodium carbonate, sodium bicarbonate, sodium borate, sodium acetate, aswell as other alkali salts of weak acids, and the like. Aqueous saltconcentrations of from 0.05%, by weight, to about 0.2%, by weight, aregenerally sufficient to speed up the formation of the hydrogel. However,rinsing of the coated devices with fresh water can take up to 24 hoursto reduce the salt content in the hydrogel sufficiently to make it safefor use under clinical conditions. Consequently, the use of catalystswhich can be removed by way of simple evaporation, or by essentiallyquantitative reaction with the isocyanate prepolymers is preferable.

An alternate method for curing of the coated prepolymer intermediate toform the hydrogel consists of submersion of the coated device in waterhaving a temperature of from about room temperature to about 80° C. fora period of from about 30 seconds to as long as about 30 minutes,depending upon the temperature of the aqueous bath. The higher the watertemperature, the lower the required dip time. This process isaccelerated by the presence of water-soluble tertiary amines, some ofwhich are illustrated above. Still another method which has been foundsuitable for accelerating the cure of the hydrogels of the presentinvention involves the use of di- or higher functional reactivepolyamines which act as catalysts and reactants for the formation of thecorresponding polyurea hydrogels. Typical diamines which can bedissolved in water include ethylenediamine, 1,4-butanediamine,1,6-hexanediamine, piperazine, dimethyl piperazines, and others.Ethylenediamine is generally preferred and has given very good results.These amines have the further advantages of being able to functionrapidly at room temperature, and they are also capable of forminginterpenetrating networks with other lubricious polymers.

After formation of the tenaciously adhering, hydrophilic, slipperyhydrogel polymer it is essential to be able to handle the medicalapparatus for the purpose of packaging, sterilizing, shipping, and thelike. For that purpose it is desirable to dehydrate the hydrogel andtransform it to a substantially dry state. This drying step is bestaccomplished by means of vacuum evaporation of the wet hydrogel. At thesame time, if the hydrogel has been manufactured in the presence of lowboiling amine catalysts it serves the useful purpose to remove anyremaining amounts thereof to make the device safe with respect toirritant chemicals for later clinical applications. The vacuum dryingstep can be performed at temperatures of from room temperature, about23.5° C., to as high as about 60° C. under a vacuum of from about 5Torr, or lower, to as high as about 200 Torr, or higher, for sufficienttime periods to remove substantially all moisture and/or volatilecontaminants.

After evaporation of moisture and any other undesired process chemicals,if any, the coated medical device is packaged in moisture-proofpackaging, for example, in properly sealed polyethylene films suitablefor this purpose. Thereafter, the device is sterilized by conventionalmeans well known in the pharmaceutical industry. The hydrogel coatingsof the present invention are sterilized by means of γ-radiation withoutcompromising the performance of the hydrophilic hydrogel coating withrespect to wear properties upon exposure to mechanical forces in blood.It is also believed that such coatings are not adversely affected bymeans of the well-known ethylene oxide sterilization procedure.

The dry and rather elastic hydrogel coatings of the present inventionrehydrate rapidly to the hydrogel upon immersion into water or salinesolution. The slipperiness as well as dynamic wear performancecharacteristics of a medical device in blood are restored andsubstantially unchanged after going through the transition phases. Afterimmersion into distilled water or saline (Ringer's) solution rehydrationis observed to take place quickly, within from less than 10 seconds tono longer than about one minute, depending upon exact proceduralconditions.

As mentioned above, a further important embodiment of the presentinvention involves the formation of dry hydrogel coatings by the removalof water, sterilization by means of γ-rays, and activation by exposureto saline solution or water just before clinical use of the device. Themost cost-effective manufacturing process of the present inventioninvolves applying a first coating of the cycloaliphatic prepolymers inan organic solvent to the device, letting it dry, and dip-coating thedried device into an aqueous solution containing a reactive diaminechain extender. After hydrogel formation, the hydrogel coating is thendried, sterilized, and reactivated at the time of clinical use.

The following examples are further illustrative of various aspects ofthe present invention. They are not deemed to be limiting in any way.The scope of the present invention is set forth by the set of claimsappended hereto. Other embodiments of the various aspects of theinvention within the scope of the claims will be evident to thoseskilled in the art. The examples describe all of the several parametersinvolved in plasma-treating the substrate polymers, preparing thehydrophilic isocyanate prepolymers of the present invention, affixingthem covalently to the treated substrates, and finally converting theattached hydrophilic top coats to the slippery, tenaciously adheringhydrogel coatings of the present invention. They also demonstrate themechanical performance of coated devices, their wear resistance, andtheir resistance to the exertion of dynamic forces in blood. Theexamples also outline a suitable procedure for the measurement of boththe dynamic behavior and permanence of the slippery, tenaciouslyadhering coatings of the present invention in blood.

Definitions

As used both in the examples and throughout the specification, thefollowing designations, symbols, terms and abbreviations have theindicated meanings:

1. Molecular weights (MW) of polyols are number average molecularweights using the experimentally determined hydroxyl numbers of thepolyols in accordance with ASTM D-4274-88, assuming that thefunctionality is known.

2. Equivalent Weights (EW) of polyols are number average equivalentweights of polyols as calculated on the basis of analytically determinedhydroxyl numbers.

3. Isocyanate Equivalent Weights (EW/NCO) are number average equivalentweights of isocyanate prepolymers calculated on the basis ofdetermination of % NCO of said prepolymers in accordance with ASTMD-4666-87 and/or equivalent test methods known in the art. Forcommercial monomeric diisocyanates, their derivatives, and HYPOLPreMA-G-50 prepolymer, published data exist.

4. "ml" denotes milliliters.

5. "Torr" denotes millimeters (mm) of mercury pressure [1 atmosphere=760Torr (mm Hg)].

6. "ppm" denotes parts per million (catalyst concentrations, metalscontents).

7. AMBERLYST 15 (ROHM & HAAS) denotes a strongly acidic macroreticularion exchange resin, generally used for non-aqueous reactions.

8. AMBERLYST A-21 (ROHM & HAAS) denotes a weakly basic macroreticularion exchange resin for removal of acidic anions from non-aqueoussystems.

9. "Urethane-grade" denotes specially dried and/or distilled solventsused as diluents for the isocyanate prepolymer reactions and prepolymercoatings solutions of the present invention (driers normally compriseUOP molecular sieves, type 4A, or equivalent materials).

10. "Silicone" Coating comprises a 2% solution of DOW CORNING MDX4-4159Fluid in n-heptane applied to the device. According to the DOW CORNINGMSDS Data Sheet, MDX-4-4159 is a solution containing 34% StoddardSolvent, 15% isopropyl alcohol, 1% dimethyl cyclosiloxanes, and 50% ofdimethoxy silyl dimethyl aminoethyl amino propyl silicone polymer (allconstituents are expressed in %, by weight).

11. "Ringer's Solution" is an isotonic saline solution comprising 0.86gm of NaCl, 0.03 gm of KCl, and 0.033 gm of CaCl₂ in 100 ml of purifiedwater.

12. "Footnotes 1 to 17" in Example 1, Table 1 describe the chemicalnature of water-soluble polyether reactants and the polyisocyanates usedfor the preparation of the hydrophilic polyether prepolymers of thepresent invention.

13. HYPOL PreMa® G-50 comprises a hydrophilic polyether prepolymer basedon IPDI (isophorone diisocyanate) available from HAMPSHIRE CHEMICALCORP., Lexington, Mass., containing approximately 0.4 milliequivalent ofNCO/gm.

14. A parison is a rod-like or tubular blank from which a ballon for amedical device is subsequently formed by blow-molding. Parisons areformed by direct extrusion of the plastic substrate material. Plasticparisons are useful as test substrates, and were used in the examplesherein, because their geometric uniformity makes them easy toplasma-treat, and because they are readily adapted to drag forcemeasurements.

15. The term hydrophilic refers to substances on which water droplets donot readily form beads on the surface of such substances, but, instead,the water droplets tend to assume a contact angle of less than 90° withthe substance, and readily form a film on the surface of the substance.Hydrophilic substances may also tend to absorb water and swell toweights much greater than their dry weights.

EXAMPLES Dynamic Drag Force Test Method

For the purpose of measuring drag forces on coated catheter tubes orballoon devices used in coronary angioplasty, it was necessary todevelop an applicable test method which gave reliable comparisons withthe prior art and between the different polymer compositions of thehydrophilic coatings of the present invention. Moreover, it was alsodecided to conduct the tests in different aqueous media, for exampledistilled water, saline solution (Ringer's Solution), blood plasma andin blood to investigate the influence of the most critical useenvironment the clinical devices can experience.

The test method for the measurement of friction and permanence for theantifriction coatings on plastic tubes of the present inventionconsisted of the following procedure:

Apparatus: INSTRON Tensile Tester, 20 lb load cell; test range 0-500 gm;cross head speed 20 inches/min up and down; 4 inch stroke, automaticcycle.

Test Fixture: Clamshell assembly with friction surface for holdingcoated plastic tube specimens. The friction surface was a commercialcleaning product SCRUNGE® available from Guardsman Products, Inc.,Consumer Products Division, Grand Rapids, Mich. and sold in major foodmarkets. The SCRUNGE® pad, consisting of ground rigid abrasive PUplastics particles surface-coated onto a flexible polyurethane foammatrix, was cut into 1×1.75 inch rectangles. The friction surfaces weremoistened with the wetting fluid and folded in half with the abrasivesurface inside. The tubular test specimen was enclosed in the foldedfriction surface and placed in the test fixture.

Test Parisons: The test parisons were thin wall plastic tubes, having alength of from about 6 inches to about 8 inches, an outside diameter(OD) of from 0.07-0.095 inch, and an inside diameter (ID) of from0.04-0.07 inch. In the event the test sample was too flexible andbuckled during the return cycle, a 0.066 inch OD braided wire rod wasinserted into the test specimen (HYTREL and other relatively flexibletubing).

Wetting Medium: The wetting media tested were distilled water, Ringer'sSolution, blood plasma, and defibrinated beef blood. The medium wasdelivered continuously to the tube at the top of the test fixture at therate of 10 to 20 drops per minute, by means of capillary tubing using asyringe pump.

Test Procedure: A braided wire shaft was placed in a test sample, asnecessary. The friction surface was wetted with appropriate test fluid.The friction surface was folded over the test sample, and thecombination of the two was placed into the test fixture and the fixturewas closed. The top end of the test sample was clamped into a clamp onthe load cell. The INSTRON test machine was started, and drag forcemeasurements were recorded at 1, 5, 10, 20, and 40 strokes.

Example 1 Rectification of Hydrophilic Polyether Precursors Based onCommercially Available Compounds for Use In Prepolymer Syntheses

Initially the starting material selected for the evaluation of PUhydrogel materials to be affixed to ammonia plasma-treated surfacesconsisted of HYPOL PreMa ®G-50, a commercially available PU hydrogelintermediate based on isophorone diisocyanate (IPDI) and a water solublecopolyether polyol. This prepolymer has a structure that appearedsuitable for the preparation of the PU hydrogels of the presentinvention. Furthermore, it was represented to yield biocompatiblepolyurea polymers that appeared quite slippery. Consequently, thisproduct was examined first in the attempt to perfect covalently-bondedhydrogels to ammonia plasma-treated substrates of interest for medicaldevices. However, it became soon apparent that this product containedvery appreciable quantities of unreacted copolyether hydroxyls.

Commercially water-soluble homopolyethers and copolyethers containingfrom one to about three hydroxyl groups per macromolecule were selectedas the first choice for starting materials for the synthesis of theprepolymers of the present invention. Most of these materials soonproved unsuitable because they contained sufficient quantities of alkalimetals or alkali metal salts to interfere with the prepolymer reactions.Consequently, the products were ion-exchange treated by dissolving themat concentrations of about 50%, by weight, in solutions of isopropylalcohol and stirring with excess quantities, in relation to estimatedlevels of metal catalyst impurities present, of about equal quantitiesof AMBERLYST 15 and AMBERLYST A-21 which had been preconditioned byimmersion in isopropyl alcohol in order to remove the alkali metals andtheir salts. Some of the homopolyethers of ethylene oxide were solids attemperatures as high as 50° to 55° C. and in those cases, theisopropanol/polyether mixture was heated to about 60° C. and maintainedthere during the ion exchange reaction. In all other cases theion-exchange treatment was conducted at from room temperature to about40° C. Alteratively, the ion exchange refining is conducted in acontinuous manner by means of mixed bed heated columns or separatecolumns using the cationic and anionic resins separately, as is wellknown in the art.

A slurry of the mixed ion exchange resins in the polyether/isopropanoldilution was agitated for a period of at least 6 hours. After that time,the resins were removed by filtration, and the ion exchange resins werewashed with a portion of isopropyl alcohol to remove entrained polyethertherefrom. For the homopolyethers from ethylene oxide, the rinse wasconducted with preheated isopropanol (˜60° C.). The rinse solutions werecombined with the original filtrate for subsequent evaporation of thediluent and water present in the polyethers. Before handling thepolyether materials at elevated temperatures in the presence of any air,they were protected by means of suitable antioxidants. For this purpose,a quantity of about 0.05%, by weight, based upon the original weight ofpolyether used for refining, of SANTONOX R (see also U.S. Pat. No.4,886,866), was added and dissolved before subsequent solvent strippingoperations.

The isopropyl alcohol was removed by distillation while blanketing thevessel with a slow stream of dry nitrogen to avoid contact with air.After distillation of the alcohol ceased, a small quantity of toluene orxylenes were added to the polyether residue and the materials weresubjected to a gradually increasing vacuum. During this procedure, waterand remaining traces of isopropanol were removed by means of azeotropicdistillation. Finally, the polyether residue was subjected to a vacuumof from 5 to 1 torr at 100 to 120° C. for a period of 2 to 3 hours undera blanket of dry nitrogen. After this time, the polyether residue wasallowed to cool to about 70° C., the vacuum was then discontinued whilethe vessel was brought to atmospheric pressure by means of blanketingwith dry nitrogen. The polyether product was alternatively removed whilestill warm or was utilized directly for the prepolymer formation step.The polyether precursor was analyzed for hydroxyl number, % H₂ O (ASTMD4672-87) and ppm alkali metals, as necessary. To avoid complicationsdue to side reactions from moisture, rehydration of the polyols wasprevented by storing them under carefully monitored anhydrousconditions.

Example 2 Preparation of Cycloaliphatic Isocyanate Prepolymers fromCommercially Available Ion-Exchanged Polyether Precursors

Because of the unsuitability of prepolymers prepared using thecommercially available water-soluble homopolyethers and copolyethers ofExample 1, it became necessary to explore the preparation andcomposition of a number of cycloaliphatic isocyanate prepolymers thatappeared useful as starting materials for the PU hydrogels of theinvention.

For the purpose of preparing the prepolymers designated A through P,presented in Table I, the polyether starting materials were heated toabout 30° C. for materials which were liquid at room temperature, and toabout 55° C. in the case of the solid homopolyethers, and the reactantswere maintained throughout the procedure under a blanket of drynitrogen. At this point the appropriate amount of catalyst, if any, wasadded to the reaction vessel. The calculated amount of diisocyanate wasthen added all at once, while the reactants were mixed thoroughly toeffect immediate homogenous reaction conditions. The ensuing exothermwas moderated if necessary to attain a reaction temperature of 70° to75° C. and the reactants were held at this temperature for a total ofabout 4 hours for the catalyzed reactions, and up to 24 hours for thenon-catalyzed systems.

It was found that the reaction between the polyethers and thecycloaliphatic isocyanates DESMODUR W and IPDI were incomplete evenafter even 24 hours at the above reaction temperatures in the absence ofcatalyst. Consequently, the prepolymer synthesis procedure waseventually amended to use tin catalysts (dibutyltin dilaurate orstannous octoate) for all prepolymer syntheses with these relativelyslow reacting diisocyanates. It was also discovered that it was easierto moderate the isocyanate reaction in the presence of aromatichydrocarbons which were co-solvents for the polyethers and thecycloaliphatic isocyanates. The solvent which proved to be most usefulwas toluene, and the reactions were generally conducted as 50% dilutionsbetween reactants and solvent, but it was also feasible to use 75%toluene and 25% reactants, if warranted. The solvent procedure alsofacilitated handling of the prepolymer materials for subsequent dilutionwith other solvents to the desired coatings compositions.

At the end of the prepolymer synthesis, the resulting products wereanalyzed for % NCO by the wet method with dibutylamine, a procedure wellknown in the art (ASTM D4666-87). For catalyzed reactions, the desiredEW/NCO agreed quite well with the calculated values. In the case ofuncatalyzed reactions, only the somewhat faster reacting aliphaticdiisocyanates (HDI) gave acceptable results. Prepolymers containingpolyethers having a propylene oxide content of at least about 15 to 20%,by weight, resulted in liquid polyether prepolymers that greatlyfacilitated handling of the coatings intermediates.

Table I, entitled "Composition of Hydrophilic PU PrepolymerIntermediates", lists the compositions, characteristics and preparationconditions of new intermediates A through P:

                                      TABLE I                                     __________________________________________________________________________    Composition of Hydrophilic PU Prepolymer Intermediates                                                       OH TO                    PHYSICAL                  STRUCTURE MOL. ISO NCO EQ     STATE                                         RUN #  POLYETHER OXIDE/FUNCT. WT. TYPE RATIO.sup.1 CATALYST PE/gm                                                                   ISO/gm CAT/gm                                                                 ROOM TEMP             __________________________________________________________________________    A    PEG 2,000.sup.2                                                                         EO - DI  2,000                                                                            W.sup.3                                                                           2:3  T-9.sup.4                                                                           125.2                                                                             24.66                                                                             0.044 Solid                   B PEG 3,400.sup.5 EO - DI  3,400 W 2:3 T-9 134.4  15.55  0.046 Solid                                                                 C PEG 8,000.sup.6                                                             EO - DI  8,000 W                                                             1:2 T-9 131.7                                                                 6.98 0.049 Solid                                                               D PLURACOL                                                                   V-10.sup.7 EO/PO                                                              - TRI 22,000 W                                                                1:2 none 64.8                                                                 1.82 none Liquid                                                               E PLURACOL                                                                   V-10.sup.9 EO/PO                                                              - TRI 22,000 W                                                                1:2 T-9 67.1 2.09                                                             0.022 Liquid                                                                   F MPEG 5,000.sup.                                                            10 EO - MONO                                                                  5,000 I 1:2 none                                                              56.2 2.50 none                                                                Solid                   G MPEG 5,000 EO - MONO  5,000 W 1:2 T-9 76.9 3.77 0.022 Solid                 H UCON 75-H 90,000.sup.11 EO/PO - DI 15,000 I 1:2 none 65.0 1.93 none                                                               Liquid                  I UCON 75-H 90,000 EO/PO - DI 15,000 W 1:2 T-9 62.5 2.19 0.022 Liquid                                                                J PEG 14,000.sup.                                                            12 EO - DI 14,000                                                             I 1:2 none 70.0                                                               2.22 none Solid                                                                K PEG 14,000 EO                                                              - DI 14,000 W 1:2                                                             T-9 70.7 2.65                                                                 0.022 Solid                                                                    L UCON 75-H                                                                  9,500.sup.13                                                                  EO/PO - DI  6,950                                                             I 1:2 none 70.3                                                               4.50 0.022 Liquid       M UCON 75-H-9,500 EO/PO - DI  6,950 W 1:2 T-9 71.5 5.39 none Liquid                                                                  N MPEG 5,000 EO                                                              - MONO  5,000 I                                                               1:2 T-12.sup.14                                                               56.2 2.50                                                                     0.00118 Solid                                                                  O UCON 75-H-90,00                                                            0 EO/PO - DI                                                                  15,000 W 1:2 T-12                                                             62.5 2.19                                                                     0.00129 Liquid                                                                 P HCC G-50                                                                   EOPO.sup.16 EO/PO                                                             - TRI ˜7,300                                                             I 1:2 T-12                                                                   73.17 6.67  .sup.                                                              0.0016.sup.16                                                                Liquid                  Q PreMA g-50.sup.17 EO/PO - TRI  I   1:2.05 none -- -- none Liquid          __________________________________________________________________________     .sup.1 Reactant ratio  Equivalents of polyether hydroxyls to equivalents      of NCO (ISO) compounds;                                                       .sup.2 Polyethylene glycol  MW ˜ 2,000;                                 .sup.3 DESMODUR W, Cycloalipathic diisocyanate available from MILES CORP.     Polymer Division; MW = 262.4, EW = 131.2;                                     .sup.4 Stannous octoate; note: all uncatalyzed DESMODUR W systems tested      contain free diisocyanate;                                                    .sup.5 Polyethylene glycol  MW ˜ 3,400;                                 .sup.6 Polyethylene glycol  MW ˜ 8,000;                                 .sup.7 Trifunctional copolyether polyol comprising trimethylolpropane         adduct of 75/25 wt. % EO/PO  MW ˜ 7320, EW ˜ 131.2;               .sup.8 Isophorone diisocyanate, available from HUELS AMERICA, Inc.; MW =      222.3, EW = 111.15;                                                           .sup.9 Trifunctional copolyether polyol comprising trimethylolpropane         adduct of 75/25 wt. % Eo/PO  MW ˜ 22,000, EW ˜ 7330;              .sup.10 Monofunctional methyl ether of polyethylene glycol  MW ˜        5,000;                                                                        .sup.11 Difunctional copolyether diol comprising 75/25 wt. % EO/PO  MW        ˜ 15,000;                                                               .sup.12 Difunctional polyethylene glycol  MW ˜ 14,000;                  .sup.13 Difunctional copolyetherdiol  MW ˜ 6,950;                       .sup.14 Dibutyltin dilaurate; note: all uncatalyzed IPDI systems tested       contain free diisocyanate;                                                    .sup.15 Precursor copolyether triol for HYPOL PreMA G50 prepolymer            (HAMPSHIRE CHEMICAL CORP.) believed to contain 75/25 wt. % of EO/PO; MW       ˜ 7,300, OH No. = 23.0;                                                 .sup.16 Systems N, O and P were also run as 50% solutions in toluene for      ease of handling and subsequent dilution to desired coatings                  concentrations and compositions;                                              .sup.17 HYPOL PreMA G50; noncatalyzed isophorone diisocyanate (IPDI)          prepolymer from copolyether (15) and IPDI  EQ ratio 1:2.05; contains free     IPDI and free hydroxyls.                                                 

Example 3 Processes for Plasma Treatment, Intermediate Coating, andFormation of PU Hydrogels

Plastic materials, having essentially no functional groups that werecapable of reaction with the isocyanate group, were used to obtaincovalent bonds with the hydrophilic hydrogel polymers of the presentinvention. Substrates such as PET, used in angioplasty balloons; HYTREL,used for catheter shafts; PE, used for various balloons; and hydrophobicnylon-11 and nylon-12 polymers, used in catheters and balloons, wereconsidered as the most important thermoplastic polymer substrates forplasma treatment with nitrogen-containing gases to affix very reactiveamino groups onto their surfaces. The formation of cohesive bonds withthe substrate surfaces is often relatively difficult to accomplish, andit is not always easy to obtain good permanence even with polyurethanesubstrates. PET and HYTREL were utilized as the plastic substratesbecause they are typical surfaces that do not lend themselves tocohesive bonding unless the surfaces are either oxidized, treated withvery aggressive solvents, or treated by other means. Test parisons ofPET and HYTREL were therefore investigated very closely. It was thepurpose of the experiment to prove that the affixation of amino groupsupon the substrate surfaces would render them very reactive with thesluggish isocyanate groups ot the hydrophillic isocyanate prepolymers ofthe present invention, which were preferable because of their greaterbiocompatibility over other more reactive PU hydrogel intermediates.

NH₃ was used as the plasma gas with the PLASMA SCIENCE PS 0350 PlasmaSurface Treatment system, previously described in detail, and theexperiment was conducted over a wide range of parameters. It was clearlyestablished that for PET tubing (parisons having an OD of about 0.095inches) use of NH₃ as the plasma gas resulted in improved adhesion ofthe PU hydrogel systems of the present invention, over an RF input rangeof from 20% power input (about 100 to 120 W) to 85% power input (about450 to 470 W), at an ammonia gas flow rate of from about 50 std ml/minto about 730 std ml/min (the maximum flow rate attainable with the PS0350 unit; higher flow rates may be attained using other apparatus),during exposure times of from about 30 seconds to about 3 minutes, andat a temperature in the range of from room temperature to about 40° C.Optimized results were observed and noted at about 100 W to about 400 Wpower input, and ammonia flow rates of from about 200 std ml/min toabout 650 std ml/min. ESCA surface analysis indicated that bestpermanence was achieved at intermediate surface concentrations of aminogroups on the PET surface. The usefulness of ammonia plasma treatmentwas also confirmed for parisons made from HYTREL. Due to the highelasticity of HYTREL, drag force measurements required the insertion ofa braided guidewire in the inside lumen of the parison to obtainreliable INSTRON readings.

The influence of the ammonia plasma treatment was tested with "Silicone"coating on PET parisons in the presence of blood as the contactenvironment and compared with the PU/PUR hydrogel from HYPOL PreMA G-50,catalyzed versions thereof, as well as combination systems comprisingPreMA G-50 and other PU/PUR hydrogel prepolymer coatings (see alsoExample 2 for synthesis of hydrophilic PU intermediates). The "Silicone"coating, was not helped by the NH₃ plasma treatment. Moreover, the"Silcone" coating did not show any kind of permanence in the presence ofblood, the main body fluid tested. In contrast, the PU/PUR hydrogelcoatings of the invention exhibited remarkably improved permanence inblood after ammonia plasma treatment. However, even the PU/PUR hydrogelswithout plasma treatment were also remarkably superior in this respectin relation to the "Silicone" coating.

Range finding tests with respect to concentration effects of the PUhydrogel intermediates (Example 2 and others) showed that suitablehydrogel coatings on the substrate surface are possible when the solidscontent of the coatings solution is within the range of from about 1.5%to about 6%, and when the dip time is from about 10 seconds to about 30seconds. However, it is within the realm and scope of the invention tostay at the lower concentration range or even below, if the dipping timeis extended, or relatively more aggressive solvents are used during theinitial dipping procedure. Various known contacting methods, includingspray coating, are also feasible. The insertion time of the device intothe coating solution has a pronounced effect upon the quality of thecoating. Other measures which influenced the coatings thickness andquality were the use of somewhat higher boiling solvents such ascellosolve acetate (UCC) and other similar slower evaporating materialsas co-solvents with the lower boiling products such as MEK, ethers, andthe like. Other materials which proved useful for the achievement ofuniform coatings included minute quantities of surface active agents,for example, TERGITOL®X-100 (UCC) and thixotropic agents, such asamorphous silicas and other materials which are known to influence thequality and application of coatings to various substrates.

A double coating procedure using the same hydrophilic PU prepolymers ordifferent prepolymers utilized in the present invention was alsoperformed. HYPOL PreMA G-50 and Prepolymer P, double-coated withPrepolymer F or Prepolymer I and others (for compositions, see Table Iof Example 2) gave even better results than the single coated versionsof G-50 or P. The usefulness of such combinations was ascertained bytesting various compositions in terms of the resulting drag forcemeasurements and cycle testing for permanence of the coated parisons inblood after the completion of the hydrogel formation.

The formation of the polyurea (PUR) hydrogel was accomplished by meansof exposing the coated device to atmospheric moisture or dip-coating thematerial in aqueous solutions of varying compositions. It was founduseful to accelerate the PUR hydrogel formation by means of tertiaryamine catalysts, reactive amine derivatives, or in the presence ofmildly basic salts to speed up the hydrogel formation. The influence ofmoisture or the combination of the coating with aqueous amine solutions,for example ethylenediamine and other polyamines, results in theformation of polyurea hydrogels which form the focal point of the PUhydrogels of the present invention. Alternatively, the PUR hydrogelformation was performed at elevated temperatures, for example attemperatures up to 80° C., to speed up the cure times and make theprocess less time-dependent and more cost-effective. PUR hydrogelformation was also alternatively conducted in the presence of othercompatible hydrophilic hydrogel polymers which are anchored to thesubstrate by means of the covalently bonded hydrophilicpolyurethane-urea (PU/PUR) "tie-coat" of the invention. Still otherprocess variations of the present invention may readily be apparent toone skilled in the art.

Example 4 Catalytic Synthesis of Hydrophilic Prepolymers

This example demonstrates the preparation of hydrophilic prepolymersprepared by the catalytic technique with 20 ppm of T-12 (dibutyltindilaurate) catalyst as a 50% solution in toluene. In all cases thewater-soluble polyether precursors were deionized by means of a slurryof AMBERLYST 15 and AMBERLYST A21 in isopropanol, and after filtration,the combined effluents were stabilized with 0.05%, by weight, ofSANTONOX R. The isopropanol was then removed by distillation underatmospheric pressure until evolution ceased, and a small quantity oftoluene was added and the distillation of toluene was continued toremove remaining isopropanol and moisture by azeotropic distillationwhile under a blanket of nitrogen throughout the refining cycle. Thematerials were then subjected to a vacuum of from about 5 Torr to about10 Torr for a period of 3 hours at from about 100° C. to about 120° C.The polyether precursors were then charged to a prepolymer reactionflask, diluted with 50%, by weight, of toluene, and the required amountof T-12 catalyst, diluted in toluene, was added, while the reactantswere kept under nitrogen at room temperature.

The proper amount of the diisocyanate, as a 50% solution in toluene, wasthen added all at once at room temperature and the exothermic adductprepolymer formation was moderated as required to keep the reactantsfrom exceeding 75° C. In the case of Prepolymer T, the initial toluenesolution of the monofunctional EO homopolyether was held at from 45° to50° C., to avoid crystalline deposition of the polyether. The reactantswere agitated continuously under a stream of dry nitrogen and maintainedat 70° to 75° C. for a period of 4 hours, and transferred into a drynitrogen flushed container after this period of time. After at least 24hours had elapsed, the NCO-terminated prepolymers were then analyzed for% NCO by the dibutylamine method. The following table shows reactantconcentrations, % NCO content based on 100% solids, and calculated andtheoretical values for % NCO. In all cases the diisocyanate chargerepresents 2 equivalents of NCO per equivalent of the hydroxyl polyetherprecursor.

                  TABLE 2                                                         ______________________________________                                        Charge Ratios and % NCO Contents for Prepolymers R, S and T                     Ingredients, gm                                                                             Prepolymer R                                                                             Prepolymer S                                                                           Prepolymer T                              ______________________________________                                        PLURACOL V-7                                                                              500.0      0          0                                             UCON 75-H-90,000 0 500.0 0                                                    MPEG 5,000 0 0 500.0                                                          Toluene, total 546.0 518.0 520.0                                              IPDI 45.6 0 22.2                                                              DESMODUR W 0 17.5 0                                                           T-12 (˜20 ppm) 0.011 0.010 0.010                                        Analysis, % NCO                                                               Actual (100% solids) 1.63 0.52 0.79                                           Theoretical, calculated 1.58 0.54 0.80                                      ______________________________________                                    

The above-described Prepolymers R, S and T correspond to catalyzedversions of P, O, and N (Table 1) and were prepared as 50% solutions intoluene. PLURACOL V-7 (BASF Corp.) is a trifunctional copolyether, whichwas used as the prepolymer precusor for R, is a 75/25%, by weight,random EO/PO polyether adduct of trimethylpropane having a OM No. of≅23.0 and a calculated EW≅2340. The prepolymers were subsequentlydiluted further to about 25% of solids with more toluene and an aliquotthereof was stored at 20° C. to 25° C. for a period of 4 months. Theprepolymers remained stable over this period of time and showed noevidence of gelation, indicating an extended shelf stability despite thepresence of tin catalyst. Prepolymer T crystallized at ambienttemperature, but could be melted readily by heating the solid to 45 to50° C. For coating of catheters, balloons and other medical devices, thetoluene solutions of the hydrophilic prepolymers were further diluted insuitable co-solvents, to a solids content of, for example, 2% by weight,before proceeding to the coating step. According to the % NCO analysisrecorded for the above prepolymers, the isocyanate reaction proceeded tocompletion when catalyzed even at very low tin catalyst levels whichwere found not to impair biocompatibility for the catheter devices.

Example 5 Evaluation of PU Hydrogels

For the purpose of evaluating the PU hydrogel coatings of the presentinvention, from which the exhibition of superior lubricity, wearperformance and durability when contacted with body fluids, is required,it was decided to deposit the coatings on plasma-treated plasticsubstrates that were known to have only a limited capability to resultin durable covalent bond fixation in the absence of pretreatments.Typical application in the medical devices field comprise the lowfriction coatings of catheter balloons and other catheter componentswhich are used in coronary angioplasty, where the devices must not onlyresist excessive wear and maintain permanence during transfer throughblocked blood vessels but must also exhibit excellent lubricity whiletraversing obstructions, and often demand complex handling duringmanipulations of the device during clinical use. Consequently, initialcoating tests were undertaken with PET and HYTREL substrates which areoften used as materials of construction for such devices, or portionsthereof. For that purpose, it was decided to utilize test parisons ofammonia plasma-treated PET tubing having dimensions of approximately 6to 8 inch length, 0.07 to 0.095 inch OD, and 0.04 to 0.07 inch ID. Forthe evaluation of many characteristic PU hydrogel coatings of thepresent invention, samples having various compositions as described inExamples 3 and 4 above were utilized. PET parisons were treated with NH₃plasma under conditions described in Example 3.

For the establishment of suitable comparison drag force testing, theplasma treatment for this particular analysis protocol was kept constantand included exposing the parisons in the HIMONT Plasma Science 0350Unit to an initial vacuum of 0.01 torr followed by application of theammonia gas plasma at a gas flow rate of 600 ml/min, at a power input of120 watts and a frequency of 13.56 MHz, at a temperature of from 25° to40° C., for a period of 3 minutes. The plasma-treated parisons were usedwithin a period of from one to three weeks to eliminate anomaly due topossible fading of the plasma treatment with extended age. Thehydrophilic PU prepolymers were diluted with MEK to a solids content of2%, by weight, and the parisons were dip-coated by insertion therein fora period of 30 seconds, and allowed to dry in a forced air hood at roomtemperature. In the case of the double coating procedure, the secondcoat was applied 60 minutes after the first coat had been affixed andthen allowed to dry again in the hood. The coatings were then exposed toa minimum of 50% relative humidity for 72 hours, before being tested inthe INSTRON drag force testing fixture described previously. The dragforces (gm) were recorded after 1, 5, 20 and 40 strokes in defibrinatedbovine blood as the contact media. It had previously been determinedthat blood is much more aggressive than saline solutions, or water, bothof which have heretofore been traditionally employed for performance anddurability testing in the catheter art. The results of Table 3 representaverages of at least 4 specimen tested in defibrinated bovine blood.

                                      TABLE 3                                     __________________________________________________________________________    Drag Forces Tests of PU Coated Ammonia Plasma-Treated PET                                DRAG FORCE in gm at NUMBER OF CYCLES (1, 5, 20, and 40)            SAMPLE TYPE                                                                              STROKE -1                                                                            STROKES -5                                                                           STROKES -20                                                                          STROKES -40                                   __________________________________________________________________________    SILICONE   40     165    225    >300                                            HYPOL PreMA ® G-50 85 90 90 120                                           A 112 185 202 203                                                             B 101 167 208 198                                                             C 65 73 92 110                                                                D 170 150 150 150                                                             E 98 132 152 164                                                              F 80 110 110 110                                                              G 112 130 130 130                                                             H 90 130 130 130                                                              I 40 60 75 85                                                                 J 150 200 225 300                                                             K 42 80 95 110                                                                L 50 80 85 90                                                                 M 70 90 110 130                                                               N 80 115 118 120                                                              O 45 55 80 90                                                                 P 75 90 95 115                                                                R 80 92 97 110                                                                S 85 100 125 135                                                            __________________________________________________________________________     Note: Specimens showing drag forces of >300 gm in blood bind in fixture       during test.                                                             

Similar experiments were run in a few instances with plasma-treatedcoatings deposited on parisons made from HYTREL® and in general similarresults were observed. The experiments show that the "Silicone" coatinggives very good results upon starting of the initial tests, but losesits lubricity very quickly when exposed to blood as the contact medium.The PU hydrogels prepared in accordance with the present inventionshowed particularly good permanence and lubricity in the presence ofblood as the medium. These phenomena, however, are unexpected and arenot predictable based on the feel of the coatings when touched, sincethe "Silicone" coating feels very "slippery" when first touched, butloses its efficacy completely during the test in bovine blood. Thehydrogel polymers of the present invention have good permanencecharacteristics apparently because of the excellent bonding with theammonia plasma-treated PET and HYTREL substrates. Preliminaryexperiments with other ammonia plasma-treated substrates such as TPU,nylons and PE suggest the obtention of similar results.

Example 6 Drag Force Determination

This example presents data for the drag force determination ofdouble-coated PU hydrogel systems with HYPOL PreMA G-50 and relatedhydrophilic prepolymers as the base coats, and various other hydrophilicprepolymers as the second coat, followed by transformation of both coatsto the highly hydrophilic PU hydrogel in the presence of atmosphericmoisture at a relative humidity of at least about 50%. Test specimenswere ammonia plasma-treated PET parisons made in accordance with theconditions described in Example 4. Both coats involved the use ofprepolymer dilutions to 2% by weight, with MEK, and the parisons wereimmersed into the first coatings solution for a period of about 30seconds, allowed to dry for about 30 minutes at room temperature in aforced air hood, whereupon the second coat was applied and allowed todry in the same manner.

The preparation of the hydrogel was conducted by exposing the coatedparisons to an atmosphere of at least 50% relative humidity for a periodof 72 hours, at room temperature, and then post-curing in a vacuum oven,maintained at a temperature of from about 60° C. to about 70° C., for aperiod of from about 1 to 2 hours, followed by measurement of the dragforce as described above. Table 4 illustrates the drag force testresults of ammonia plasma-treated double-coated PET parisons andspecifies the prepolymer coatings systems. The numbers are averages offour determinations for each coating composition.

                                      TABLE 4                                     __________________________________________________________________________    Drag Force Tests of Double-Coated PET Parisons                                         DRAG FORCE in gm at NUMBER OF CYCLES (1, 5, 20, and 40)              SAMPLE TYPE                                                                            STROKE -1                                                                            STROKES -5                                                                            STROKES -20                                                                          STROKES -40                                    __________________________________________________________________________    PreMA ® G-50                                                                       85     90      100    120                                              G-50 + B 121 192 225 235                                                      G-50 + C 53 60 66 79                                                          G-50 + D 70 86 98 97                                                          G-50 + E 50 88 118 148                                                        G-50 + F 40 40 40 40                                                          G-50 + G 108 152 168 175                                                      G-50 + H 86 200 235 255                                                       G-50 + I 35 60 75 86                                                          G-50 + J 85 110 122 150                                                       G-50 + K 100 148 155 190                                                      G-50 + L 50 80 85 90                                                          R + T 50 60 85 90                                                             S + T 60 72 87 115                                                          __________________________________________________________________________

The combination of two coats of the hydrogels of the present inventionexhibited synergistic effects with respect to the quality of thecoatings. In particular it was surprising that the monofunctionalisocyanate adduct shown as compounds F and T (precursor monofunctionalhomopolyether of EO having a MW of ˜5,000) appeared particularlyeffective as a second coat. This material may act as a chain-stopper forthe hydrogel polymer. Difunctional isocyanate adducts also gave improvedresults. Of particular importance is the efficacy of the second coatwith respect to durability and good lubricity of the hydrogel coating inblood over an extended cycle of up to 40 strokes, representing asignificantly longer duration.

Example 7 Comparative Test of Inventive and Prior Art Coatings inSeveral Media

Very surprisingly, the hydrophilic hydrogels affixed to plasma-treatedsurfaces according to the present invention showed no unusual resultswhen tested in media typically utilized by others to test the propertiesof low friction coatings. Previous commercial materials had usually beentested in water, or Ringer's Solution. The efficacy of the covalentlybonded PU/PUR hydrogel coatings was comparatively tested in the presenceof water, Ringer's solution and blood media. Dynamic testing of the PETand HYTREL® parisons was conducted in the presence of bovine blood todetermine whether there existed unusual interactions betweencommercially available coatings and the coatings of the presentinvention in the presence of blood as the test media. This was done inview of observations by others that the lubricity of many coatedcatheters of the prior art lacked permanence.

The results are presented in Table 5:

                                      TABLE 5                                     __________________________________________________________________________    Comparison Drag Force Tests in Various Media                                             DRAG FORCE in gm at NUMBER OF CYCLES (1, 5, 20, 40)                PET PARISON                                                                              STROKE -1                                                                            STROKES -5                                                                           STROKES -20                                                                          STROKES -40                                   __________________________________________________________________________    TEST MEDIUM                                                                     UNCOATED PET                                                                  Water 142 150 160 160                                                         Ringer's Solution 70 75 75 75                                                 Blood 230 220 220 220                                                         UNTREATED PET                                                                 "Silicone" Coating                                                            Water 45 40 44 45                                                             Ringer's Solution 59 59 60 60                                                 Blood 45 165 225 >300                                                         PLASMA-TREATED                                                                PET                                                                           HYPOL PreMA ® G-50                                                        Water 100 100 100 100                                                         Ringer's Solution 54 54 67 75                                                 Blood 77 79 91 105                                                            "Silicone" Coating                                                            Water 35 40 43 45                                                             Ringer's Solution 55 55 55 60                                                 Blood 35 155 230 >300                                                       __________________________________________________________________________     Note: Specimens showing drag forces of >300 gm in blood bind in fixture       during testing.                                                          

The above comparative tests illustrate that the uncoated PET parisonswhen tested in the test fixture previously described herein exhibitedrelatively high drag forces in water, low drag forces in Ringer'sisotonic saline solution, and consistently high drag forces in blood.The "Silicone" coating gave low drag forces in both water and salinesolution even after 40 strokes, but was not at all effective in blood.This tends to confirm clinical experience.

HYPOL PreMA® G-50, a typical PU/PUR hydrogel of the present invention,gave good results in Ringer's solution and moderately acceptable resultsin water. However, the efficacy of the PU hydrogels in blood was clearlydemonstrated. All PU/PUR hydrogel polymer intermediates synthesized wereinvestigated in blood to verify the surprising lubricity and permanenceof such coatings when deposited upon substrates that cannot reactreadily with isocyanates or form physical (noncovalent) bonds with therelatively slow reacting biocompatible hydrophilic PU intermediates ofthe present invention. Similarly excellent results were obtained withthe PU hydrogel coatings of the present invention when deposited onnitrogen-containing plasma-treated substrates of thermoplastic PU,nylon, HYTREL, and dual oxygen- and nitrogen- gas plasma-treated PEpolymer substrates, or alternatively, oxygen or air plasma-treated, oroxygen or air plasma-treated polymer substrates in the presence of argon(Ar) gas followed by fairly rapid treatment with a stream of gaseousammonia without plasma.

Example 8 Radiation Exposure of Coatings

The behavior of the PU/PUR hydrogel coatings of the present inventionwhen exposed to γ-radiation, as is used to sterilize medical devicesprior to clinical use, was evaluated. For this purpose a limited numberof ammonia plasma-treated PET parisons that were coated with severalrepresentative PU/PUR hydrogels were tested under dynamic conditions inblood before and after exposure to γ-radiation. The radiation dosage wasselected upon the basis of previous experience with respect tosterilization of medical devices. Table 6 shows clearly that radiationdoes not interfere with the performance of the low friction coatings ofthe present invention when immersed in blood:

                                      TABLE 6                                     __________________________________________________________________________    Effect of Gamma Radiation on Performance of Coatings                                       DRAG FORCE in gm at NUMBER OF CYCLES (1, 5, 20, 40)              PLASMA-TREATED PET                                                                         STROKE -1                                                                            STROKES -5                                                                           STROKES -20                                                                          STROKES -40                                 __________________________________________________________________________    RADIATION TREATMENT                                                             BEFORE GAMMA                                                                  HYPOL PreMa ® G-50 62 73  85 107                                          G-50 + C 75 84 110 120                                                        G-50 + E 55 86 100 105                                                        Prepolymer C 66 102 108 112                                                   Prepolymer E 64 96 107 117                                                    AFTER GAMMA                                                                   HYPOL PreMA ® G-50 44 66 108 140                                          G-50 + C 40 76 104 110                                                        G-50 + E 60 104 104 120                                                       Prepolymer C 100  120 130 130                                                 Prepolymer E 52 102 109 111                                                 __________________________________________________________________________     Note: Samples from 2% solution; Radiation; 2.5 to 3.8 megarads; Test          Medium: Blood.                                                           

Example 9 Reactivation of Coatings

After the preparation of the final hydrogel which is covalently bondedto the nitrogen containing plasma-treated substrate, or to anaminosilane coated metal part, medical devices coated with coatings ofthe present invention are preferably dried, packaged in materials whichare not moisture-permeable, and sterilized before use under clinicalconditions. Drying of the device requires complete evaporation of thewater from the hydrogel barrier coating. Because the dry hydrophilicPU/PUR base hydrogel is elastomeric, the coating does not flake or crackduring drying. This can be accomplished by vacuum-drying of theapparatus under conditions well known in the art. For the purpose ofexamining rehydration, the coated parisons were vacuum-dried understandard conditions, heat-sealed inside a polyethylene film of suitablethickness and then exposed to γ-radiation to sterilize the specimens.After a period of 2 weeks the dry parisons were exposed to moisture byinsertion into Ringer's solution or distilled water. The hydrogel testspecimens appeared rehydrated within 10 to 15 seconds, or less. Uponsubsequent measurement of the dynamic drag force in blood, excellent lowforce readings were observed and the coatings were as wear-resistant asfreshly prepared materials.

We claim:
 1. A material bearing thereon a coating of a lubricious,hydrated hydrophilic polyurethane-polyurea hydrogel, said material beingproduced by a process comprising the steps of:a) making a surface of ametal substrate reactive by affixing reactive chemical functional groupsthereto, at least a portion of which are amine-containing groups; b)coating a reactive metal substrate surface which results from step (a)with a first coating comprising a hydrophilic polyurethane prepolymerintermediate, containing terminal isocyanate groups, such that at leasta portion of said terminal isocyanate groups are reacted with and arecovalently bonded to said reactive chemical functional groups on saidsubstrate surface, forming covalent polyurea bonds therewith, resultingin the formation of a tie coat of a polyurethane-polyureahydrogel-forming polymer, on said substrate surface, that adheres tosaid substrate surface, and wherein at least a portion of said terminalisocyanate groups of said polyurethane prepolymer intermediate arepresent in said polyurethane-polyurea hydrogel-forming polymer such thatthey remain free to react with other species; and c) coating a tie coatof the first-coated substrate surface which results from step (b) with asecond coating comprising a moisture-containing, hydrogel-formingcompound or mixture, which contains isocyanate-reactive functionalgroups, such that a barrier coat of a lubricious, hydrated hydrogel isformed upon the application of said second coating to said tie coat;wherein said moisture of said hydrogel-forming compound or mixture isbound with said polyurethane-polyurea hydrogel-forming polymer of saidtie coat to form a hydrogel of said barrier coat, on said tie coat, suchthat said hydrogel is a polyurethane-polyurea polymer hydrogel; andwherein said isocyanate-reactive functional groups of saidhydrogel-forming compound or mixture are reacted with and are covalentlybonded to at least a portion of said terminal isocyanate groups of saidpolyurethane-polyurea hydrogel-forming polymer that remain free to reactwith other species, thereby directly attaching saidpolyurethane-polyurea polymer hydrogel to said tie coat and thus alsoindirectly attaching to said substrate surface.
 2. The materialaccording claim 1 wherein said substrate is pre-treated , prior tomaking a surface thereof reactive, to clean said substrate.
 3. Thematerial according to claim 2 wherein said pretreatment of saidsubstrate is by a method comprising:at least one of: washing saidsubstrate with at least one organic solvent; and washing said substratewith an aqueous solution of at least one of neutral, anionic andcationic surfactants, and combinations thereof; followed by washing saidsubstrate with water, and drying.
 4. The material according to claim 3wherein said organic solvent is selected from the group consisting ofalcohols, ketones, hydrocarbons, chlorinated hydrocarbons, ethers,petroleum ethers, cleaning spirits, and combinations thereof.
 5. Thematerial according to claim 4 wherein said alcohols include methanol,ethanol, and isopropanol; said ketones include acetone and methylethylketone; said hydrocarbons include pentanes and n-hexane; saidchlorinated hydrocarbons include methylene chloride and1,1,1-trichlorethane; and said ethers include diisopropyl ether,dioxane, and tetrahydrofuran.
 6. The material according to claim 3wherein said pre-treatment is performed for a period of time of fromabout 10 seconds to about 10 minutes.
 7. The material according to claim1 wherein said metal substrate is selected from the group consisting ofstainless steel, titanium, alloys of steel, nickel, titanium,molybdenum, cobalt, and chromium, and nitinol (nickel-titanium alloy),and vitallium (cobalt-chromium alloy).
 8. The material according toclaim 1 wherein said reactive chemical functional groups includeamino-silane groups.
 9. The material according to claim 8 wherein saidamino-silane groups have amino terminal groups at one end and silaneterminal groups at an opposite end, such that said silane terminalgroups are attached to said metal substrate surface, and said aminoterminal groups are free to react with other species.
 10. The materialaccording to claim 9 wherein lower all groups having from 2 to about 8carbons are positioned between said silane terminal groups and saidamino terminal groups.
 11. The material according to claim 8 whereinsaid amino-silane groups are affixed to said surface of said metalsubstrate by chemical treatment thereof.
 12. The material according toclaim 11 wherein said chemical treatment of said metal substrate is witha compound selected from the group consisting ofγ-aminopropyltriethoxysilane, γ-aminopropyltrimethoxysilane,β-aminoethyl-γ-aminopropyltrimethoxysilane, and a prehydrolyzedaminoalkyl silanol.
 13. The material according to claim 12 wherein saidcomposition contains from about 0.5% to about 3%, by weight, of saidselected compound in water.
 14. The material according to claim 1wherein said hydrophilic polyurethane prepolymer intermediate is formedby the reaction of a water-soluble polyether polyol, or copolyetherpolyol, and an organic polyisocyanate.
 15. The material according toclaim 14 wherein said organic polyisocyanate is selected from the groupconsisting of aliphatic, cycloaliphatic, araliphatic, aromatic, andheterocyclic polyisocyanates.
 16. The material according to claim 15wherein said aliphatic, cycloaliphatic, araliphatic, aromatic, orheterocyclic polyisocyanate is a diisocyanate or a derivative thereof.17. The material according to claim 16 wherein said hydrophilicpolyurethane prepolymer intermediate is formed by reacting saidpolyether polyol or copolyether polyol with an excess of organicpolyisocyanate.
 18. The material according to claim 14 wherein saidreaction which leads to the formation of hydrophilic polyurethanepolymer is performed at temperature of up to about 90° C.
 19. Thematerial according to claim 18 wherein the temperature is from about 50°C. to about 70° C.
 20. The material according to claim 14 wherein thehydrophilic polyurethane polymer formation reaction is performed in anon-aqueous solution containing a total solids content of from about 20%to about 80%, by weight.
 21. The material according to claim 20 whereina non-aqueous solvent of said solution is selected from the groupconsisting of aromatic hydrocarbons, ketones, ethers, esters,chlorinated alkanes, and mixtures thereof.
 22. The material according toclaim 21 wherein said aromatic hydrocarbons include benzene, toluene andxylenes; said ketones include methylethyl ketone; said ethers includemethyl tert, butyl ether, tetrahydrofurane and dioxane; said estersinclude methylethoxy acetate, methylisopropoxy acetate, ethyl acetate,butyl acetate, and ethyl formate; and said chlorinated alkanes include1,1,1-trichloroethane.
 23. The material according to claim 14 performedin the presence of a catalyst to promote reaction between said polyetherpolyol or said copolyether polyol and said organic polyisocyanate. 24.The material according to claim 23 wherein said catalyst is atin-containing compound selected from the group consisting of stannousacylates, dialkytin dicarboxylates, and dialkytin oxides.
 25. Thematerial according to claim 24 wherein said tin-containing compound isselected from the group consisting of stannous octoate, stannous oleate,dibutyltin dilaurate, dimethyltin dilaurate, and dioctyltin oxide. 26.The material according to claim 24 wherein catalyst is at aconcentration of from about 5 ppm to about 300 ppm.
 27. The materialaccording to claim 1 wherein said first coating is applied to saidreactive surface of said substrate as a first coating solutioncontaining from about 1% to about 25% by weight of prepolymerintermediate solids in a nonaqueous solvent selected from the groupconsisting of aromatic hydrocarbons, ketones, ethers, tetrahydrofurane,dioxane, esters, chloroalkanes, C₅ and C₆ alkanes, methylene dichloride,acetone and mixtures thereof.
 28. The material according to claim 27wherein said prepolymer intermediate solids are from about 1.5% to about8%, by weight.
 29. The material according to claim 27 wherein said firstcoating solution is applied to said reactive surface of said substrateby a method selected from the group consisting of dip-coating,continuous coating and spray coating.
 30. The material according toclaim 27 further comprising removing the solvent from said first coatingsolution after application of said first coating solution to saidsubstrate.
 31. The material according to claim 30 wherein solventremoval is by evaporation thereof.
 32. The material according to claim 1wherein said moisture-containing, hydrogel-forming compound or mixtureof said second coating is selected from the group consisting of liquidwater, saline solution, water vapor, and a high moisture content air orgas stream.
 33. The material according to claim 32 wherein saidmoisture-containing, hydrogel-forming compound of said second coating iswater.
 34. The material according to claim 1 wherein said coating of alubricious, hydrated hydrophilic polyurethane-polyurea polymer hydrogelhas a thickness of from about 1 mil to about 5 mils.
 35. The materialaccording to claim 1 wherein steps (a) and (b) are completed within aperiod of time of two months from one another.
 36. The materialaccording to claim 1 wherein said process for producing said materialfurther comprises heating said first-coated substrate, bearing said tiecoat resulting from said first coating, to a temperature of from about40° C. to about 75° C. to further promote covalent bond formationbetween terminal isocyanate groups and terminal reactive groups on saidsubstrate surface, before application of said second coating.
 37. Thematerial according to claim 1 further comprising a slip additive addedto said hydrophilic polyurethane prepolymer intermediate.
 38. Thematerial according to claim 1 wherein said hydrogel barrier coat of ahydrophilic polyurethane-polyurea hydrogel has a water content of atleast about 70% by weight.
 39. The material according to claim 38wherein said water content is from about 85% to about 90% by weight. 40.The material according to claim 1 wherein the formation of said hydrogelbarrier coat in step (c) is performed in the presence of a hydrogelformation promoting catalyst.
 41. The material according to claim 40wherein said hydrogel formation promoting catalyst is a tertiary amine.42. The material according to claim 41 wherein said tertiary amine isselected from the group consisting of trimethylamine, triethylamine,tripropylamine, and triisopropylamine.
 43. The material according toclaim 40 wherein said catalyst is in aqueous solution.
 44. The materialaccording to claim 43 wherein said aqueous solution contains from about0.03% to about 0.3% by weight of catalyst.
 45. The material according toclaim 1 wherein the formation of said hydrogel barrier coat in step (c)is performed in the presence of a compound selected from the groupconsisting of aliphatic, cycloaliphatic, araliphatic, and heterocyclicdiamines, and inorganic diamines, to form a chain-extended hydrogel. 46.The material according to claim 45 wherein said inorganic diamine isselected from the group consisting of hydrazine and substitutedhydrazine.
 47. The material according to claim 1 wherein the formationof said hydrogel barrier coat in step (c) is performed in the presenceof a dual catalytic and chain-extending compound containing anisocyanate reactant group and a catalytic moiety.
 48. The materialaccording to claim 47 wherein said dual compound containing anisocyanate reactant group and a catalytic moiety is an organic aminecontaining a tertiary amine group and at least one of a primary and asecondary amine group.
 49. The material according to claim 47 whereinsaid dual compound is ethylenediamine.
 50. The material according toclaim 1 wherein the formation of said hydrogel barrier coat in step (c)is performed in the presence of a basic inorganic salt selected from thegroup consisting of sodium carbonate, sodium bicarbonate, sodium borate,and sodium acetate, to cure said hydrogel.
 51. The material according toclaim 50 wherein said basic inorganic salt is in an aqueous solutionhaving a salt concentration of from about 0.05% to about 0.2% by weight.52. The material according to claim 51 further including a step ofrinsing the resulting hydrogel coating with water to remove saidinorganic salt.
 53. A material bearing thereon a dried coating of ahydrophilic polyurethane-urea hydrogel, said material being produced bya process comprising:performing the steps of the process according toclaim 1; and d) further performing a step of drying said lubricious,hydrated hydrophilic polyurethane-polyurea polymer hydrogel, to form adried coating thereof.
 54. The material according to claim 53 whereinsaid step of drying said second coating is performed by vacuumevaporation.
 55. The material according to claim 54 wherein said vacuumevaporation is performed at a pressure in the range of from about 3 Torrto about 250 Torr.
 56. The material according to claim 55 wherein saidvacuum evaporation is performed at a temperature in the range of fromabout 20° C. to about 60° C.
 57. A material bearing thereon a coating ofa lubricious, hydrated hydrophilic, water-containingpolyurethane-polyurea hydrogel, wherein said coating is formed by thereactivation of a dried hydrogel coating thereof, said coating beingreactivated from a dried state, said material being produced by aprocess comprising:performing the steps of the process according toclaim 53; and e) further performing a step of re-exposing said driedhydrogel coating formed in step (d) to an aqueous fluid to reactivatesaid dried hydrogel coating to a lubricious, hydrated hydrogel coating.58. The material according to claim 57 wherein said aqueous fluid isselected from the group consisting of liquid water, saline solution,water vapor, and a high moisture content air or gas stream.
 59. Asterilized coating of a reactivatable, dried, hydrophilicpolyurethane-polyurea hydrogel, on the surface of a medical devicefabricated from a metallic substrate, said sterilized coating beingproduced by a process comprising:a) making at least a portion of anouter surface of said metallic substrate from which said medical deviceis fabricated, chemically reactive by affixing reactive chemicalfunctional groups thereto; b) coating the resulting reactive outersurface of said substrate with a first coating comprising a hydrophilicpolyurethane-urea prepolymer intermediate, which is capable of forming apolyurethane-polyurea hydrogel-forming polymer, and which containsterminal isocyanate groups, such that at least a portion of saidterminal isocyanate groups are reacted with and are covalently bonded tosaid reactive chemical functional groups on said surface of saidsubstrate, forming covalent polyurea bonds therewith, resulting in theformation of a tie coat of a polyurethane-polyurea hydrogel-formingpolymer, that adheres to said reactive outer surface of said substrate,and wherein at least a portion of said terminal isocyanate groups ofsaid polyurethane-urea prepolymer intermediate are present in saidpolyurethane-polyurea hydrogel-forming polymer, such that they remainfree to react with other species; c) coating said tie coat with a secondcoating comprising a moisture-containing hydrogel-forming compound,further containing isocyanate-reactive chemical functional groups, suchthat a barrier coat of a lubricious, hydrated hydrogel is formed uponthe application of said second coating to said tie coat of said firstcoated substrate;wherein said isocyanate-reactive functional groups ofsaid moisture-containing hydrogel-forming compound are reacted with andare covalently bonded to at least a portion of said terminal isocyanategroups of said polyurethane-polyurea hydrogel-forming polymer thatremain free to react with other species, to form a hydrated, hydrophilicpolyurethane-polyurea polymer hydrogel, that is directly adhering tosaid tie coat, and thus also indirectly adhering to said substratesurface; d) drying said hydrated, hydrophilic polyurethane-polyureahydrogel coating formed in step (c) to form a dried hydrogel coatingthereof; and e) sterilizing the resulting coated medical device, bearingsaid dried hydrogel coating of step (d).
 60. The material according toclaim 59 wherein said step of sterilization is performed by means ofexposing said dried hydrogel-coated medical device to gamma-radiation.